Fused pyrimidine compounds as brd4 and jak2 dual inhibitors and methods for use thereof

ABSTRACT

The present invention relates to fused pyrimidine compounds, particularly pyrrolopyrimidine and thienopyrimidine compounds and derivatives thereof, pharmaceutical compositions thereof, and methods of inhibiting BRD4 and/or JAK2, as well as methods of treating various diseases and conditions, such as cancer and leukemia, with such compounds. Bromodomain binding and JAK activity are included.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.62/428,756, filed on Dec. 1, 2016, the disclosure of which is herebyincorporated by reference in its entirety for all purposes

FIELD OF THE INVENTION

The present disclosure relates to fused pyrimidine compounds,particularly pyrrolopyrimidine compounds and derivatives thereof,pharmaceutical composition thereof, and methods of inhibiting BRD4 andJAK2, as well as methods of treating various disease and conditions,with such compounds.

BACKGROUND OF THE INVENTION

Bromodomain (BRD)-containing proteins are essential for the recognitionof acetylated lysine (KAc) residues of histones during transcriptionalactivation. BRDs regulate the transcription of various oncogenes, suchas c-Myc and Bcl-2. Thus, BRDs have emerged as promising drug targetsfor a number of disease pathways that are characterized by changes inthe epigenetic cell signature. To date, only a few structurally diverseBRD inhibitors have been reported, all of which specifically target theKAc recognition sites of the bromodomain and extra terminal (BET) familyof proteins (BRD2, BRD3, BRD4, and BRDT), each containing two tandemBRDs. BET-inhibitors exert a broad spectrum of desirable biologicaleffects such as anticancer and anti-inflammatory properties. Recently,it was discovered that the BRD of BETs interact with diverse kinaseinhibitors.

Janus kinase 2 (JAK2) is a non-receptor tyrosine kinase which catalyzesthe transfer of a phosphate group from a nucleoside triphosphate donor,such as ATP, to tyrosine residues in proteins. JAK2 is involved invarious processes such as cell growth, development, differentiation orhistone modifications. Accordingly, gain-of-function mutations in JAK2has been implicated in cancer cell growth and progression, formation ofmetastasis, and tumor neovascularization.

Dual targeting of bromondomains and kinases, such as BRD4 and JAK2,offers a promising new strategy to treat conditions mediated bybromodomain activity and tyrosine kinase activity.

SUMMARY OF THE INVENTION

Disclosed herein are fused pyrimidine compounds, particularlypyrrolopyrimidine compounds and derivatives thereof, which inhibit theactivity of at least one bromodomain, the activity of at least one Januskinase, or a combination thereof. In particular embodiments, thecompounds inhibit the activity of BRD4, the activity of JAK2 tyrosinekinase, or a combination thereof. Thus, in particular embodiments, thedisclosure provides for compounds which are dual BRD4 and JAK2 tyrosinekinase inhibitors.

In embodiments, the present disclosure provides for compounds accordingto formula (I):

or a pharmaceutically acceptable salt or solvate thereof;wherein:

R¹ is H, halogen, alkyl, haloalkyl, hydroxyl, alkylhydroxyl, alkoxy,haloalkoxy, or —NR^(a)R^(b);

R² and R³ are each independently H or alkyl;

R⁴ and R⁵ are each independently H, halogen, hydroxyl or alkyl;

R⁶ and R⁷ are each independently H, halogen, hydroxyl or alkyl; oralternatively, R⁶ and R³ together or R⁷ and R³ together forms asaturated, unsaturated, or partially saturated, 5- or 6-membered ring;

ring A and ring B are each aromatic;

Z¹ is C or N;

Z² is C, CR⁸, or N;

Z³ and Z⁴ are each independently C, CR⁸, N, or S;

provided that at least one of Z¹, Z², Z³, and Z⁴ is N or S and at mosttwo of Z¹, Z², Z³, and Z⁴ is N;

R⁸ is H, halogen, or alkyl;

L is a bond or —CH₂—;

W is —S(O)_(m)R⁹, —P(O)₂R⁹, or —P(═S)₂R⁹;

R⁹ is alkyl, cycloalkyl, or aryl, wherein cycloalkyl and aryl isoptionally substituted with one or more of halogen or alkyl;

Y is selected from

in Y¹ and Y², R¹⁰ and R¹⁴ are each independently H, halogen, hydroxyl,alkyl, or alkoxy;

in Y¹, R¹¹, R¹² and R¹³ are each independently H, halogen, alkyl,alkoxy, heterocyclyl, —(CH₂)_(n)—C(O)NR^(a)R^(c),—(CH₂)_(n)—NR^(a)C(O)R^(d), —(CH₂)_(n)—C(O)(CH₂)_(n)—, —NR^(a)R^(b),—NR^(a)-alkylene-NR^(a)R^(b) or—(CH₂)_(n)—C(O)NR^(a)-alkylene-NR^(a)R^(b); or

in Y², R¹¹ is H, halogen, hydroxyl or alkyl;

in Y², ring C is a monocyclic, bicyclic, or tricyclic 5- to 12-memberedheterocycle containing at least one atom selected from N, O, or S,wherein ring C is optionally substituted with R¹⁵;

R^(a) and R^(b) are each independently, H or alkyl;

R^(c) is H, alkyl, -alkyl-NR^(a)R^(b), or heterocyclyl;

R^(d) is alkyl, -alkyl-NR^(a)R^(b), or heterocyclyl;

wherein hetercocycyl in R¹¹, R¹², R¹³, R^(c), and R^(d) is eachindependently optionally substituted with R¹⁵;

R¹⁵ is halogen, hydroxyl, alkyl, alkylhydroxyl, oxo, —C(O)-alkyl,—C(O)OR^(a); —NR^(a)C(O)-alkyl, —(CH₂)_(n)—C(O)NR^(a)R^(b),—NR^(a)R^(b); or —S(O)_(n)-alkyl,

n is 0, 1, or 2; and

m is 0, 1, or 2;

wherein the compound is not

In embodiments, Z² is N and Z¹, Z³, and Z⁴ are each independently C orCR⁸.

In embodiments, Z¹ is N and Z², Z³, and Z⁴ are each independently C orCR⁸.

In embodiments, Z¹ and Z³ are each N, and Z² and Z⁴ are eachindependently C or CR⁸.

In embodiments, Z¹ and Z⁴ are each N, and Z³ and Z⁴ are eachindependently C or CR⁸.

In embodiments, the compound of formula (I) has the structure accordingto formula (II)

or a pharmaceutically acceptable salt or solvate thereof.

In embodiments, W is —S(O)₂R⁹.

In embodiments, R⁹ is C₁-C₆ alkyl or C₃-C₆ alkyl, each optionallysubstituted.

In embodiments, L is a bond.

In embodiments, the compound of formula (I) has the structure accordingto formula (III)

In embodiments, R² and R³ are each H or C₁-C₃ alkyl.

In embodiments, R⁴ and R⁵ are each H.

In embodiments, R⁶ and R⁷ are each independently H or halogen.

In embodiments, R⁶ and R³ together forms a saturated, unsaturated, orpartially saturated, 5- or 6-membered ring.

In embodiments, R⁶ and R³ together forms a saturated 5-membered ring.

In embodiments, R¹⁰ and R¹⁴ are each H.

In embodiments, at least one of R¹¹ and R¹³ is a halogen.

In embodiments, Y is Y¹.

In embodiments, one of R¹¹, R¹² and R¹³ is an optionally substitutedheterocyclyl.

In embodiments, the heterocyclyl is selected from piperidine,piperazine, hexahydropyrimidine, morpholine, tetrahydropyran, thiane, orthiomorpholine, each optionally substituted.

In embodiments, the heterocyclyl is a bicycle.

In embodiments, the heterocyclyl is selected from

each of which is optionally substituted with R¹⁵.

In embodiments, one of R¹¹, R¹² and R¹³ is —(CH₂)_(n)—C(O)NR^(a)R^(c),—(CH₂)_(n)—NR^(a)C(O)R^(d), —(CH₂)_(n)—C(O)(CH₂)—, —NR^(a)R^(b),—NR^(a)-alkylene-NR^(a)R^(b), or—(CH₂)_(n)—C(O)NR^(a)-alkylene-NR^(a)R^(b).

In embodiments, one of R¹¹, R¹² and R¹³ is —NR^(a)-alkylene-NR^(a)R^(b)or —(CH₂)_(n)—C(O)NR^(a)-alkylene-NR^(a)R^(b).

In embodiments, wherein Y is Y².

In embodiments, Y² is selected from:

each of which is optionally substituted with R¹⁵; and R¹⁶ is H or C₁-C₃alkyl.

In embodiments, R⁹ is C₁-C₆ alkyl or C₃-C₆ alkyl, each optionallysubstituted.

In embodiments, the compound of formula (I) has the structure accordingto formula (IV)

or a pharmaceutically acceptable salt or solvate thereof.

In embodiments, W is —S(O)₂R⁹.

In embodiments, R⁹ is C₁-C₆ alkyl or C₃-C₆ alkyl, each optionallysubstituted.

In embodiments, L is a bond.

In embodiments, the compound of formula (I) has the structure has astructure according to formula (V)

or a pharmaceutically acceptable salt or solvate thereof.

In embodiments, R² and R³ are each H or C₁-C₃ alkyl. In embodiments, R⁴and R⁵ are each H. In embodiments, R⁶ and R⁷ are each independently H orhalogen. In embodiments, R¹⁰ and R¹⁴ are each H.

In embodiments, at least one of R¹¹ and R¹³ is a halogen. Inembodiments, Y is Y¹. In embodiments, one of R¹¹, R¹² and R¹³ is anoptionally substituted heterocyclyl. In embodiments, the heterocyclyl isselected from piperidine, piperazine, hexahydropyrimidine, morpholine,tetrahydropyran, thiane, or thiomorpholine, each optionally substituted.In embodiments, the heterocyclyl is a bicycle.

In embodiments, the heterocyclyl is selected from

each of which is optionally substituted with R¹⁵.

In embodiments, one of R11, R12 and R13 is —(CH2)n-C(O)NRaRc,—(CH2)n-NRaC(O)Rd, —(CH2)n-C(O)(CH2)n-, —NRaRb, —NRa-alkylene-NRaRb, or—(CH2)n-C(O)NRa-alkylene-NRaRb;

In embodiments, one of R11, R12 and R13 is —NRa-alkylene-NRaRb or—(CH2)n-C(O)NRa-alkylene-NRaRb.

In embodiments, Y is Y2. In embodiments, Y² is selected from:

each of which is optionally substituted with R¹⁵; andR¹⁶ is H or C₁-C₃ alkyl.

In embodiments, the compound has a structure according to formula (X):

or a pharmaceutically acceptable salt or solvate thereof;wherein:

Z¹, Z² and Z³ are each S, N or CR⁸, provided that at least one of Z¹, Z²or Z³ is N or S and at most two of Z¹, Z² or Z³ is N or S;

ring A and ring B are each aromatic;

V is

L is a bond or —CH₂—;

W is —S(O)_(m)R⁹, —P(O)₂R⁹, or —P(═S)₂R⁹;

R², R^(2a) and R³ are each independently H or alkyl;

R⁴ and R⁵ are each independently H, halogen, hydroxyl or alkyl;

R⁶ and R⁷ are each independently H, halogen, hydroxyl or alkyl; or

alternatively, R⁶ and R³ together or R⁷ and R³ together forms asaturated, unsaturated, or partially saturated, 5- or 6-membered ring;

R⁸ is H, halogen, or alkyl;

R⁹ is alkyl, cycloalkyl, or aryl, wherein cycloalkyl and aryl isoptionally substituted with one or more of halogen or alkyl;

Y is selected from

in Y¹ and Y², R¹⁰ and R¹⁴ are each independently H, halogen, hydroxyl oralkyl;

in Y¹, R¹¹, R¹² and R¹³ are each independently H, halogen, alkyl,alkoxy, heterocyclyl, —(CH₂)_(n)—C(O)NR^(a)R^(c),—(CH₂)_(n)—NRaC(O)R^(d), —(CH₂)_(n)—C(O)(CH₂)_(n)—, —NR^(a)R^(b),—NR^(a)-alkylene-NR^(a)R^(b) or—(CH₂)_(n)—C(O)NR^(a)-alkylene-NR^(a)R^(b); or

in Y², R¹¹ is H, halogen, hydroxyl or alkyl;

in Y², ring C is a monocyclic, bicyclic, or tricyclic 5- to 12-memberedheterocycle containing at least one atom selected from N, O, or S,wherein ring C is optionally substituted with

in Y³, R¹⁰, R¹¹, R¹³ and R¹⁴ are each H, halogen, hydroxyl or alkyl;

in Y³, R¹⁶ is H or alkyl;

in Y⁴, R¹⁰, R¹³ and R¹⁴ are each H, halogen, hydroxyl or alkyl;

in Y⁴, Z⁴ is NR^(a) or O;

in Y³ and Y⁴, M is a bond or —CH₂—;

R^(a) and R^(b) are each independently, H or alkyl;

R^(c) is H, alkyl, -alkyl-NR^(a)R^(b), or heterocyclyl;

R^(d) is alkyl, -alkyl-NR^(a)R^(b), or heterocyclyl;

wherein hetercocycyl in R¹¹, R¹², R¹³, R^(c), and R^(d) is eachindependently optionally substituted with R¹⁵;

R¹⁵ is halogen, hydroxyl, alkyl, alkylhydroxyl, oxo, —C(O)-alkyl,—C(O)OR^(a); —NR^(a)C(O)-alkyl, —(CH₂)_(n)—C(O)NR^(a)R^(b),—NR^(a)R^(b); or —S(O)_(n)-alkyl,

n is 0, 1, or 2; and

m is 0, 1, or 2.

In embodiments, Z¹, Z² and Z³ are each S or CR⁸, wherein exactly one ofZ¹, Z² or Z³ is S.

In embodiments, Z¹ is S.

In embodiments, Z³ is S.

In embodiments, V is V².

In embodiments, R^(2a) is H and R³ is alkyl.

In embodiments, R^(2a) is H and R³ is C₃-C₆ cycloalkyl.

In embodiments, V is

In embodiments, V is V¹.

In embodiments, W is —S(O)₂R⁹.

In embodiments, R⁹ is C₁-C₆ alkyl or C₃-C₆ alkyl, each optionallysubstituted.

In embodiments, L is a bond.

In embodiments, R⁴ and R⁵ are each H.

In embodiments, R⁶ and R⁷ are each independently H or halogen.

In embodiments, R⁶ and R³ together forms a saturated, unsaturated, orpartially saturated, 5- or 6-membered ring.

In embodiments, R⁶ and R³ together forms a saturated 5-membered ring.

In embodiments, Y is Y¹.

In embodiments, one of R¹¹, R¹² and R¹³ is an optionally substitutedheterocyclyl.

In embodiments, the heterocyclyl is selected from piperidine,piperazine, hexahydropyrimidine, morpholine, tetrahydropyran, thiane, orthiomorpholine, each optionally substituted.

In embodiments, the heterocyclyl is a bicycle.

In embodiments, the heterocyclyl is selected from

each of which is optionally substituted with R¹⁵.

In embodiments, one of R¹¹, R¹² and R¹³ is —(CH₂)_(n)—C(O)NR^(a)R^(c),—(CH₂)_(n)—NR^(a)C(O)R^(d), —(CH₂)_(n)—C(O)(CH₂)_(n)—, —NR^(a)R^(b),—NR^(a)-alkylene-NR^(a)R^(b), or—(CH₂)_(n)—C(O)NR^(a)-alkylene-NR^(a)R^(b).

In embodiments, one of R¹¹, R¹² and R¹³ is —NR^(a)-alkylene-NR^(a)R^(b)or —(CH₂)_(n)—C(O)NR^(a)-alkylene-NR^(a)R^(b).

In embodiments, Y is Y².

In embodiments, Y² is selected from:

each of which is optionally substituted with R¹⁵; and R¹⁶ is H or C₁-C₃alkyl.

In embodiments, Y is Y³.

In embodiments, R¹⁰, R¹¹, R¹³ and R¹⁴ are each H.

In embodiments, R¹⁶ is H or methyl.

In embodiments, M is —CH₂—.

In embodiments, wherein Y is Y⁴.

In embodiments, R¹⁰, R¹³ and R¹⁴ are each H.

In embodiments, Z⁴ is NH or NCH₃.

In embodiments, the compound is selected from:

or a pharmaceutically acceptable salt or solvate thereof.

In embodiments, the compound is

or a pharmaceutically acceptable salt or solvate thereof.

In embodiments, one or more compounds disclosed herein haveBRD4-inhibiting activity corresponding to an IC₅₀ of 10 μM or less. Insome embodiments, the compounds having BRD4-inhibiting activity do nothave JAK2 tyrosine kinase inhibiting activity.

In embodiments, one or more compounds disclosed herein have JAK2tyrosine kinase inhibiting activity corresponding to an IC₅₀ of 1.0 μMor less. In some embodiments, the compounds having JAK2 tyrosine kinaseinhibiting activity do not have BRD4 inhibiting activity.

In embodiments, one or more compounds disclosed herein haveBRD4-inhibiting activity corresponding to an IC₅₀ of 10 μM or less andJAK2 tyrosine kinase inhibiting activity corresponding to an IC₅₀ of 1.0μM or less.

In one embodiment, the present disclosure provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier or apharmaceutically acceptable excipient and a compound disclosed herein ora pharmaceutically acceptable salt or solvate thereof.

In other embodiments, the present disclosure provides for method oftreating a disease or condition responsive to the inhibition of abromodomain-containing protein comprising administering to the subjectin need thereof, a therapeutically effective amount of a compound ofdisclosed herein, or a pharmaceutically acceptable salt thereof. Inembodiments, the bromodomain-containing protein is BRD4. In embodiments,wherein the subject is human. In embodiments, the disease or conditionis cancer. In embodiments, the cancer is selected from one or more ofthe group consisting of bladder cancer, brain cancer, breast cancer,colorectal cancer, cervical cancer, gastrointestinal cancer,genitourinary cancer, head and neck cancer, lung cancer, ovarian cancer,pancreatic cancer, prostate cancer, renal cancer, skin cancer, andtesticular cancer. In embodiments, the present disclosure provides for amethod of treating a disease or condition responsive to the inhibitionof a JAK2 tyrosine kinase comprising administering to the subject inneed thereof, a therapeutically effective amount of a compound disclosedherein, or a pharmaceutically acceptable salt thereof. In embodiments,wherein the subject is human. In embodiments, the disease or conditionis cancer. In embodiments, the cancer is selected from one or more ofthe group consisting of bladder cancer, brain cancer, breast cancer,colorectal cancer, cervical cancer, gastrointestinal cancer,genitourinary cancer, head and neck cancer, lung cancer, ovarian cancer,pancreatic cancer, prostate cancer, renal cancer, skin cancer, andtesticular cancer.

DETAILED DESCRIPTION

While the following terms are believed to be well understood by one ofordinary skill in the art, the following definitions are set forth tofacilitate explanation of the presently disclosed subject matter.

Throughout the present specification, numerical ranges are provided forcertain quantities. It is to be understood that these ranges compriseall subranges therein. Thus, the range “from 50 to 80” includes allpossible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70,etc.). Furthermore, all values within a given range may be an endpointfor the range encompassed thereby (e.g., the range 50-80 includes theranges with endpoints such as 55-80, 50-75, etc.).

The term “a” or “an” refers to one or more of that entity; for example,“a BRD4 and JAK2 dual inhibitor” refers to one or more inhibitors or atleast one inhibitor. As such, the terms “a” (or “an”), “one or more” and“at least one” are used interchangeably herein. In addition, referenceto “an inhibitor” by the indefinite article “a” or “an” does not excludethe possibility that more than one of the inhibitors is present, unlessthe context clearly requires that there is one and only one of theinhibitors.

As used herein, the verb “comprise” as is used in this description andin the claims and its conjugations are used in its non-limiting sense tomean that items following the word are included, but items notspecifically mentioned are not excluded. The present invention maysuitably “comprise”, “consist of”, or “consist essentially of”, thesteps, elements, and/or reagents described in the claims.

It is further noted that the claims may be drafted to exclude anyoptional element. As such, this statement is intended to serve asantecedent basis for use of such exclusive terminology as “solely”,“only” and the like in connection with the recitation of claim elements,or the use of a “negative” limitation.

The term “pharmaceutically acceptable salts” include those obtained byreacting the active compound functioning as a base, with an inorganic ororganic acid to form a salt, for example, salts of hydrochloric acid,sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonicacid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid,hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylicacid, mandelic acid, carbonic acid, etc. Those skilled in the art willfurther recognize that acid addition salts may be prepared by reactionof the compounds with the appropriate inorganic or organic acid via anyof a number of known methods.

The term “treating” means one or more of relieving, alleviating,delaying, reducing, reversing, improving, or managing at least onesymptom of a condition in a subject. The term “treating” may also meanone or more of arresting, delaying the onset (i.e., the period prior toclinical manifestation of the condition) or reducing the risk ofdeveloping or worsening a condition.

An “effective amount” means the amount of a formulation according to theinvention that, when administered to a patient for treating a state,disorder or condition is sufficient to effect such treatment. The“effective amount” will vary depending on the active ingredient, thestate, disorder, or condition to be treated and its severity, and theage, weight, physical condition and responsiveness of the mammal to betreated.

The term “therapeutically effective” applied to dose or amount refers tothat quantity of a compound or pharmaceutical formulation that issufficient to result in a desired clinical benefit after administrationto a patient in need thereof.

All weight percentages (i.e., “% by weight” and “wt. %” and w/w)referenced herein, unless otherwise indicated, are measured relative tothe total weight of the pharmaceutical composition.

As used herein, “substantially” or “substantial” refers to the completeor nearly complete extent or degree of an action, characteristic,property, state, structure, item, or result. For example, an object thatis “substantially” enclosed would mean that the object is eithercompletely enclosed or nearly completely enclosed. The exact allowabledegree of deviation from absolute completeness may in some cases dependon the specific context. However, generally speaking, the nearness ofcompletion will be so as to have the same overall result as if absoluteand total completion were obtained. The use of “substantially” isequally applicable when used in a negative connotation to refer to thecomplete or near complete lack of action, characteristic, property,state, structure, item, or result. For example, a composition that is“substantially free of” other active agents would either completely lackother active agents, or so nearly completely lack other active agentsthat the effect would be the same as if it completely lacked otheractive agents. In other words, a composition that is “substantially freeof” an ingredient or element or another active agent may still containsuch an item as long as there is no measurable effect thereof.

As used herein, “inhibit” it conjugations thereof refers to a reductionin activity of a target, e.g., BRD4 or JAK2 tyrosine kinase. In someembodiments, “inhibit” refers to substantially complete loss of functionor a reduction in activity (e.g., by about 1% or more). Thus, inhibitcan include a reduction of activity within the range of from 1% to about100%, including a values and subranges therein.

The terms below, as used herein, have the following meanings, unlessindicated otherwise:

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo radical.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

“Imino” refers to the ═NH substituent.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the ═O substituent.

“Thioxo” refers to the ═S substituent.

“Alkyl” or “alkyl group” refers to a fully saturated, straight orbranched hydrocarbon chain radical having from one to twelve carbonatoms, and which is attached to the rest of the molecule by a singlebond. Alkyls comprising any number of carbon atoms from 1 to 12 areincluded. An alkyl comprising up to 12 carbon atoms is a C₁-C₁₂ alkyl,an alkyl comprising up to 10 carbon atoms is a C₁-C₁₀ alkyl, an alkylcomprising up to 6 carbon atoms is a C₁-C₆ alkyl and an alkyl comprisingup to 5 carbon atoms is a C₁-C₅ alkyl. A C₁-C₅ alkyl includes C₅ alkyls,C₄ alkyls, C₃ alkyls, C₂ alkyls and C₁ alkyl (i.e., methyl). A C₁-C₆alkyl includes all moieties described above for C₁-C₅ alkyls but alsoincludes C₆ alkyls. A C₁-C₁₀ alkyl includes all moieties described abovefor C₁-C₅ alkyls and C₁-C₆ alkyls, but also includes C₇, C₈, C₉ and C₁₀alkyls. Similarly, a C₁-C₁₂ alkyl includes all the foregoing moieties,but also includes C₁₁ and C₁₂ alkyls. Non-limiting examples of C₁-C₁₂alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl,i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl,n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless statedotherwise specifically in the specification, an alkyl group can beoptionally substituted.

“Alkylene” or “alkylene chain” refers to a fully saturated, straight orbranched divalent hydrocarbon chain radical, and having from one totwelve carbon atoms. Non-limiting examples of C₁-C₁₂ alkylene includemethylene, ethylene, propylene, n-butylene, ethenylene, propenylene,n-butenylene, propynylene, n-butynylene, and the like. The alkylenechain is attached to the rest of the molecule through a single bond andto the radical group through a single bond. The points of attachment ofthe alkylene chain to the rest of the molecule and to the radical groupcan be through one carbon or any two carbons within the chain. Unlessstated otherwise specifically in the specification, an alkylene chaincan be optionally substituted.

“Alkenyl” or “alkenyl group” refers to a straight or branchedhydrocarbon chain radical having from two to twelve carbon atoms, andhaving one or more carbon-carbon double bonds. Each alkenyl group isattached to the rest of the molecule by a single bond. Alkenyl groupcomprising any number of carbon atoms from 2 to 12 are included. Analkenyl group comprising up to 12 carbon atoms is a C₂-C₁₂ alkenyl, analkenyl comprising up to 10 carbon atoms is a C₂-C₁₀ alkenyl, an alkenylgroup comprising up to 6 carbon atoms is a C₂-C₆ alkenyl and an alkenylcomprising up to 5 carbon atoms is a C₂-C₅ alkenyl. A C₂-C₅ alkenylincludes C₅ alkenyls, C₄ alkenyls, C₃ alkenyls, and C₂ alkenyls. A C₂-C₆alkenyl includes all moieties described above for C₂-C₅ alkenyls butalso includes C₆ alkenyls. A C₂-C₁₀ alkenyl includes all moietiesdescribed above for C₂-C₅ alkenyls and C₂-C₆ alkenyls, but also includesC₇, C₈, C₉ and C₁₀ alkenyls. Similarly, a C₂-C₁₂ alkenyl includes allthe foregoing moieties, but also includes C₁₁ and C₁₂ alkenyls.Non-limiting examples of C₂-C₁₂ alkenyl include ethenyl (vinyl),1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl,1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl,1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl,7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl,6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl,4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl,1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl,6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl,1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl,6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and11-dodecenyl. Unless stated otherwise specifically in the specification,an alkyl group can be optionally substituted.

“Alkenylene” or “alkenylene chain” refers to a straight or brancheddivalent hydrocarbon chain radical, having from two to twelve carbonatoms, and having one or more carbon-carbon double bonds. Non-limitingexamples of C₂-C₁₂ alkenylene include ethene, propene, butene, and thelike. The alkenylene chain is attached to the rest of the moleculethrough a single bond and to the radical group through a single bond.The points of attachment of the alkenylene chain to the rest of themolecule and to the radical group can be through one carbon or any twocarbons within the chain. Unless stated otherwise specifically in thespecification, an alkenylene chain can be optionally substituted.

“Alkynyl” or “alkynyl group” refers to a straight or branchedhydrocarbon chain radical having from two to twelve carbon atoms, andhaving one or more carbon-carbon triple bonds. Each alkynyl group isattached to the rest of the molecule by a single bond. Alkynyl groupcomprising any number of carbon atoms from 2 to 12 are included. Analkynyl group comprising up to 12 carbon atoms is a C₂-C₁₂ alkynyl, analkynyl comprising up to 10 carbon atoms is a C₂-C₁₀ alkynyl, an alkynylgroup comprising up to 6 carbon atoms is a C₂-C₆ alkynyl and an alkynylcomprising up to 5 carbon atoms is a C₂-C₅ alkynyl. A C₂-C₅ alkynylincludes C₅ alkynyls, C₄ alkynyls, C₃ alkynyls, and C₂ alkynyls. A C₂-C₆alkynyl includes all moieties described above for C₂-C₅ alkynyls butalso includes C₆ alkynyls. A C₂-C₁₀ alkynyl includes all moietiesdescribed above for C₂-C₅ alkynyls and C₂-C₆ alkynyls, but also includesC₇, C₈, C₉ and C₁₀ alkynyls. Similarly, a C₂-C₁₂ alkynyl includes allthe foregoing moieties, but also includes C₁₁ and C₁₂ alkynyls.Non-limiting examples of C₂-C₁₂ alkenyl include ethynyl, propynyl,butynyl, pentynyl and the like. Unless stated otherwise specifically inthe specification, an alkynyl group can be optionally substituted.

“Alkynylene” or “alkynylene chain” refers to a straight or brancheddivalent hydrocarbon chain radical, having from two to twelve carbonatoms, and having one or more carbon-carbon triple bonds. Non-limitingexamples of C₂-C₁₂ alkynylene include ethynylene, propargylene and thelike. The alkynylene chain is attached to the rest of the moleculethrough a single bond and to the radical group through a single bond.The points of attachment of the alkynylene chain to the rest of themolecule and to the radical group can be through one carbon or any twocarbons within the chain. Unless stated otherwise specifically in thespecification, an alkynylene chain can be optionally substituted.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl, alkenyl or alknyl radical as defined above containing one totwelve carbon atoms. Unless stated otherwise specifically in thespecification, an alkoxy group can be optionally substituted.

“Alkylamino” refers to a radical of the formula —NHR_(a) or —NR_(a)R_(a)where each R_(a) is, independently, an alkyl, alkenyl or alkynyl radicalas defined above containing one to twelve carbon atoms. Unless statedotherwise specifically in the specification, an alkylamino group can beoptionally substituted.

“Alkylcarbonyl” refers to the —C(═O)R_(a) moiety, wherein R_(a) is analkyl, alkenyl or alkynyl radical as defined above. A non-limitingexample of an alkyl carbonyl is the methyl carbonyl (“acetal”) moiety.Alkylcarbonyl groups can also be referred to as “Cw-Cz acyl” where w andz depicts the range of the number of carbon in R_(a), as defined above.For example, “C₁-C₁₀ acyl” refers to alkylcarbonyl group as definedabove, where R_(a) is C₁-C₁₀ alkyl, C₁-C₁₀ alkenyl, or C₁-C₁₀ alkynylradical as defined above. Unless stated otherwise specifically in thespecification, an alkylcarbonyl group can be optionally substituted.

“Alkylhydroxyl” refers to a hydroxyl, as defined above, connected to analkyl, as described above, through a single bond. Non-limiting examplesof a an alkylhydroxyl include 1-hydroxypropyl, 1-hydroxybutyl, and thelike.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 18 carbon atoms and at least one aromatic ring. For purposes ofthis invention, the aryl radical can be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which can include fused or bridgedring systems. Aryl radicals include, but are not limited to, arylradicals derived from aceanthrylene, acenaphthylene, acephenanthrylene,anthracene, azulene, benzene, chrysene, fluoranthene, fluorene,as-indacene, s-indacene, indane, indene, naphthalene, phenalene,phenanthrene, pleiadene, pyrene, and triphenylene. Unless statedotherwise specifically in the specification, the term “aryl” is meant toinclude aryl radicals that are optionally substituted.

“Aralkyl” or “arylalkyl” refers to a radical of the formula —R_(b)—R_(c)where R_(b) is an alkylene group as defined above and R_(c) is one ormore aryl radicals as defined above, for example, benzyl, diphenylmethyland the like. Unless stated otherwise specifically in the specification,an aralkyl group can be optionally substituted.

“Aralkenyl” or “arylalkenyl” refers to a radical of the formula—R_(b)—R_(c) where R_(b) is an alkenylene group as defined above andR_(c) is one or more aryl radicals as defined above. Unless statedotherwise specifically in the specification, an aralkenyl group can beoptionally substituted.

“Aralkynyl” or “arylalkynyl” refers to a radical of the formula—R_(b)—R_(c) where R_(b) is an alkynylene group as defined above andR_(c) is one or more aryl radicals as defined above. Unless statedotherwise specifically in the specification, an aralkynyl group can beoptionally substituted.

“Cylic” refers to a ring structure. Cyclic rings can comprise from 3 to20 atoms in the ring, wherein the atoms which form the ring can includeat least one carbon and/or at least one heteroatom. Cyclic rings includemonocyclic, bicyclic, and tricyclic ring systems, which may includefused or bridged ring systems. Unless stated otherwise specifically inthe specification, a cyclic group can be optionally substituted.

“Carbocyclyl,” “carbocyclic ring” or “carbocycle” refers to a ringstructure, wherein the atoms which form the ring are each carbon.Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring.Carbocyclic rings include aryls and cycloalkyl, cycloalkenyl andcycloalkynyl as defined herein. Unless stated otherwise specifically inthe specification, a carbocyclyl group can be optionally substituted.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclicfully saturated hydrocarbon radical consisting solely of carbon andhydrogen atoms, which can include fused or bridged ring systems, havingfrom three to twenty carbon atoms, preferably having from three to tencarbon atoms, and which is attached to the rest of the molecule by asingle bond. Monocyclic cycloalkyl radicals include, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. Polycyclic cycloalkyl radicals include, for example,adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl,and the like. Unless otherwise stated specifically in the specification,a cycloalkyl group can be optionally substituted.

“Cycloalkenyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,having one or more carbon-carbon double bonds, which can include fusedor bridged ring systems, having from three to twenty carbon atoms,preferably having from three to ten carbon atoms, and which is attachedto the rest of the molecule by a single bond. Monocyclic cycloalkenylradicals include, for example, cyclopentenyl, cyclohexenyl,cycloheptenyl, cycloctenyl, and the like. Polycyclic cycloalkenylradicals include, for example, bicyclo[2.2.1]hept-2-enyl and the like.Unless otherwise stated specifically in the specification, acycloalkenyl group can be optionally substituted.

“Cycloalkynyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,having one or more carbon-carbon triple bonds, which can include fusedor bridged ring systems, having from three to twenty carbon atoms,preferably having from three to ten carbon atoms, and which is attachedto the rest of the molecule by a single bond. Monocyclic cycloalkynylradicals include, for example, cycloheptynyl, cyclooctynyl, and thelike. Unless otherwise stated specifically in the specification, acycloalkynyl group can be optionally substituted.

“Cycloalkylalkyl” refers to a radical of the formula —R_(b)—R_(d) whereR_(b) is an alkylene, alkenylene, or alkynylene group as defined aboveand R_(d) is a cycloalkyl, cycloalkenyl, cycloalkynyl radical as definedabove. Unless stated otherwise specifically in the specification, acycloalkylalkyl group can be optionally substituted.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and thelike. Unless stated otherwise specifically in the specification, ahaloalkyl group can be optionally substituted.

“Haloalkenyl” refers to an alkenyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,1-fluoropropenyl, 1,1-difluorobutenyl, and the like. Unless statedotherwise specifically in the specification, a haloalkenyl group can beoptionally substituted.

“Haloalkynyl” refers to an alkynyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,1-fluoropropynyl, 1-fluorobutynyl, and the like. Unless stated otherwisespecifically in the specification, a haloalkenyl group can be optionallysubstituted.

“Haloalkoxy” refers to an alkoxy radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,1-fluoropropoxy, 1-fluorobutoxy, and the like. Unless stated otherwisespecifically in the specification, a haloalkoxyl group can be optionallysubstituted.

“Heterocyclyl,” “heterocyclic ring” or “heterocycle” refers to a stable3- to 20-membered non-aromatic ring radical which consists of two totwelve carbon atoms and from one to six heteroatoms selected from thegroup consisting of nitrogen, oxygen and sulfur. Heterocyclycl orheterocyclic rings include heteroaryls as defined below. Unless statedotherwise specifically in the specification, the heterocyclyl radicalcan be a monocyclic, bicyclic, tricyclic or tetracyclic ring system,which can include fused or bridged ring systems; and the nitrogen,carbon or sulfur atoms in the heterocyclyl radical can be optionallyoxidized; the nitrogen atom can be optionally quaternized; and theheterocyclyl radical can be partially or fully saturated. Examples ofsuch heterocyclyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, a heterocyclyl group can be optionally substituted.

“Heterocyclylalkyl” refers to a radical of the formula —R_(b)—R_(e)where R_(b) is an alkylene group as defined above and R_(e) is aheterocyclyl radical as defined above. Unless stated otherwisespecifically in the specification, a heterocycloalkylalkyl group can beoptionally substituted.

“Heterocyclylalkenyl” refers to a radical of the formula —R_(b)—R_(e)where R^(b) is an alkenylene group as defined above and R_(e) is aheterocyclyl radical as defined above. Unless stated otherwisespecifically in the specification, a heterocycloalkylalkenyl group canbe optionally substituted.

“Heterocyclylalkynyl” refers to a radical of the formula —R_(b)—R_(c)where R_(b) is an alkynylene group as defined above and R_(e) is aheterocyclyl radical as defined above. Unless stated otherwisespecifically in the specification, a heterocycloalkylalkynyl group canbe optionally substituted.

“N-heterocyclyl” refers to a heterocyclyl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heterocyclyl radical to the rest of the molecule is through anitrogen atom in the heterocyclyl radical. Unless stated otherwisespecifically in the specification, a N-heterocyclyl group can beoptionally substituted.

“Heteroaryl” refers to a 5- to 20-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur, and at least one aromatic ring. For purposes of this invention,the heteroaryl radical can be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which can include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical can be optionally oxidized; the nitrogen atom can be optionallyquaternized. Examples include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwisespecifically in the specification, a heteroaryl group can be optionallysubstituted.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. Unless stated otherwise specifically inthe specification, an N-heteroaryl group can be optionally substituted.

“Heteroarylalkyl” refers to a radical of the formula —R_(b)—R_(f) whereR_(b) is an alkylene chain as defined above and R_(f) is a heteroarylradical as defined above. Unless stated otherwise specifically in thespecification, a heteroarylalkyl group can be optionally substituted.

“Heteroarylalkenyl” refers to a radical of the formula —R_(b)—R_(f)where R_(b) is an alkenylene, chain as defined above and R_(f) is aheteroaryl radical as defined above. Unless stated otherwisespecifically in the specification, a heteroarylalkenyl group can beoptionally substituted.

“Heteroarylalkynyl” refers to a radical of the formula —R_(b)—R_(f)where R_(b) is an alkynylene chain as defined above and R_(f) is aheteroaryl radical as defined above. Unless stated otherwisespecifically in the specification, a heteroarylalkynyl group can beoptionally substituted.

“Thioalkyl” refers to a radical of the formula —SR_(a) where R_(a) is analkyl, alkenyl, or alkynyl radical as defined above containing one totwelve carbon atoms. Unless stated otherwise specifically in thespecification, a thioalkyl group can be optionally substituted.

The term “substituted” used herein means any of the above groups (i.e.,alkyl, alkylene, alkenyl, alkenylene, alkylhydroxyl, alkynyl,alkynylene, alkoxy, alkylamino, alkylcarbonyl, thioalkyl, aryl, aralkyl,carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl,haloalkyl, haloalkoxy, heterocyclyl, N-heterocyclyl, heterocyclylalkyl,heteroaryl, N-heteroaryl and/or heteroarylalkyl) wherein at least onehydrogen atom is replaced by a bond to a non-hydrogen atoms such as, butnot limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atomin groups such as hydroxyl groups, alkoxy groups, and ester groups; asulfur atom in groups such as thiol groups, thioalkyl groups, sulfonegroups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groupssuch as amines, amides, alkylamines, dialkylamines, arylamines,alkylarylamines, diarylamines, N-oxides, imides, and enamines; a siliconatom in groups such as trialkylsilyl groups, dialkylarylsilyl groups,alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatomsin various other groups. “Substituted” also means any of the abovegroups in which one or more hydrogen atoms are replaced by ahigher-order bond (e.g., a double- or triple-bond) to a heteroatom suchas oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen ingroups such as imines, oximes, hydrazones, and nitriles. For example,“substituted” includes any of the above groups in which one or morehydrogen atoms are replaced with —NR_(g)R_(h), —NR_(g)C(═O)R_(h),—NR_(g)C(═O)NR_(g)R_(h), —NR_(g)C(═O)OR_(h), —NR_(g)SO₂R_(h),—OC(═O)NR_(g)R_(h), —OR_(g), —SR_(g), —SOR_(g), —SO₂R_(g), —OSO₂R_(g),—SO₂OR_(g), ═NSO₂R_(g), and —SO₂NR_(g)R_(h). “Substituted” also meansany of the above groups in which one or more hydrogen atoms are replacedwith —C(═O)R_(g), —C(═O)OR_(g), —C(═O)NR_(g)R_(h), —CH₂SO₂R_(g),—CH₂SO₂NR_(g)R_(h). In the foregoing, R_(g) and R_(h) are the same ordifferent and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy,alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl,cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl,heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl,N-heteroaryl and/or heteroarylalkyl. “Substituted” further means any ofthe above groups in which one or more hydrogen atoms are replaced by abond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo,alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl,cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl,haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl,heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkylgroup. In addition, each of the foregoing substituents can also beoptionally substituted with one or more of the above substituents.

As used herein, the symbol “

” (hereinafter can be referred to as “a point of attachment bond”)denotes a bond that is a point of attachment between two chemicalentities, one of which is depicted as being attached to the point ofattachment bond and the other of which is not depicted as being attachedto the point of attachment bond. For example, “

” indicates that the chemical entity “XY” is bonded to another chemicalentity via the point of attachment bond. Furthermore, the specific pointof attachment to the non-depicted chemical entity can be specified byinference. For example, the compound CH₃—R³, wherein R³ is H or “

” infers that when R³ is “XY”, the point of attachment bond is the samebond as the bond by which R³ is depicted as being bonded to CH₃.

The following description includes information that may be useful inunderstanding the present invention. It is not an admission that any ofthe information provided herein is prior art or relevant to thepresently claimed inventions, or that any publication specifically orimplicitly referenced is prior art.

Compounds of the Present Disclosure

In embodiments, the present disclosure provides for a compound offormula (I′):

or a pharmaceutically acceptable salt or solvate thereof;wherein:

R¹ is H, halogen, alkyl, haloalkyl, hydroxyl, alkylhydroxyl, alkoxy,haloalkoxy, or —NR^(a)R^(b);

R² and R³ are each independently H or alkyl;

R⁴ and R⁵ are each independently H, halogen, hydroxyl or alkyl;

one of R⁶, R⁷ or R⁸ is

and remaining R⁶, R⁷ or R⁸ are each independently H, halogen, hydroxylor alkyl;

when R⁸ is V¹, R⁶ and R³ together or R⁷ and R³ together can optionallyform a saturated, unsaturated, or partially saturated, 5- or 6-memberedring;

when R⁶ is V¹, R⁸ and R³ together can optionally form a saturated,unsaturated, or partially saturated, 5- or 6-membered ring;

ring A and ring B are each aromatic;

Z¹ is C or N;

Z² is C, CR⁸, or N;

Z³ and Z⁴ are each independently C, CR⁸, N, or S;

provided that at least one of Z¹, Z², Z³, and Z⁴ is N or S and at mosttwo of Z¹, Z², Z³, and Z⁴ is N;

R⁸ is H, halogen, or alkyl;

L is a bond or —CH₂—;

W is —S(O)_(m)R⁹, —P(O)₂R⁹, or —P(═S)₂R⁹;

R⁹ is alkyl, cycloalkyl, or aryl, wherein cycloalkyl and aryl isoptionally substituted with one or more of halogen or alkyl;

Y is selected from

-M-carbocyclyl (Y⁵), or -M-heterocyclyl (Y⁶);

in Y¹ and Y², R¹⁰ and R¹⁴ are each independently H, halogen, hydroxyl,alkyl, alkoxy, —NR^(a)R^(a);

in Y¹, R¹¹, R¹² and R¹³ are each independently H, halogen, alkyl,alkoxy, —(CH₂)_(n)-heterocyclyl, —(CH₂)_(n)—C(O)NR^(a)R^(c),—(CH₂)_(n)—NR^(a)C(O)R^(d), —(CH₂)_(n)—C(O)(CH₂)_(n)—, —NR^(a)R^(b),—NR^(a)-alkylene-NR^(a)R^(b), or—(CH₂)_(n)—C(O)NR^(a)-alkylene-NR^(a)R^(b); or

in Y², R¹¹ is H, halogen, hydroxyl or alkyl;

in Y², ring C is a monocyclic, bicyclic, or tricyclic 5- to 12-memberedheterocycle containing at least one atom selected from N, O, or S,wherein ring C is optionally substituted with R¹⁵;

in Y⁵, carbocycle is monocyclic or bicyclic ring, optionally substitutedwith one or more R²⁰;

in Y⁶, heterocycle is monocyclic or bicyclic ring containing at leastone atom selected from O, S, or N, optionally substituted with one ormore R²⁰;

R²⁰ is each H, halogen, hydroxyl, alkyl, or oxo CN, —C(O)NR^(a)R^(b),aralykyl, aryl, heteroaralkyl, heteroaryl;

in Y⁵ and Y⁶, M is a bond or —CH₂—;

R^(a) and R^(b) are each independently, H or alkyl;

R^(c) is H, alkyl, -alkyl-NR^(a)R^(b), or heterocyclyl;

R^(d) is alkyl, -alkyl-NR^(a)R^(b), or heterocyclyl;

wherein hetercocycyl in R¹¹, R¹², R¹³, R^(c), and R^(d) is eachindependently optionally substituted with R¹⁵;

R¹⁵ is halogen, hydroxyl, alkyl, alkylhydroxyl, oxo, —C(O)-alkyl,—C(O)OR^(a); —NR^(a)C(O)-alkyl, —(CH₂)_(n)—C(O)NR^(a)R^(b),—NR^(a)R^(b); or —S(O)_(n)-alkyl,

n is 0, 1, or 2; and

m is 0, 1, or 2.

In embodiments, the present disclosure provides for compounds accordingto formula (I):

or a pharmaceutically acceptable salt or solvate thereof;wherein:

R¹ is H, halogen, alkyl, haloalkyl, hydroxyl, alkylhydroxyl, alkoxy,haloalkoxy, or —NR^(a)R^(b);

R² and R³ are each independently H or alkyl;

R⁴ and R⁵ are each independently H, halogen, hydroxyl or alkyl;

R⁶ and R⁷ are each independently H, halogen, hydroxyl or alkyl; or

alternatively, R⁶ and R³ together or R⁷ and R³ together forms asaturated, unsaturated, or partially saturated, 5- or 6-membered ring;

ring A and ring B are each aromatic;

Z¹ is C or N;

Z² is C, CR⁸, or N;

Z³ and Z⁴ are each independently C, CR⁸, N, or S;

provided that at least one of Z¹, Z², Z³, and Z⁴ is N or S and at mosttwo of Z¹, Z², Z³, and Z⁴ is N;

R⁸ is H, halogen, or alkyl;

L is a bond or —CH₂—;

W is —S(O)_(m)R⁹, —P(O)₂R⁹, or —P(═S)₂R⁹;

R⁹ is alkyl, cycloalkyl, or aryl, wherein cycloalkyl and aryl isoptionally substituted with one or more of halogen or alkyl;

Y is selected from

in Y¹ and Y², R¹⁰ and R¹⁴ are each independently H, halogen, hydroxyl,alkyl, or alkoxy;

in Y¹, R¹¹, R¹² and R¹³ are each independently H, halogen, alkyl,alkoxy, heterocyclyl, —(CH₂)_(n)—C(O)NR^(a)R^(c),—(CH₂)_(n)—NR^(a)C(O)R^(d), —(CH₂)_(n)—C(O)(CH₂)_(n)—, —NR^(a)R^(b),—NR^(a)-alkylene-NR^(a)R^(b) or—(CH₂)_(n)—C(O)NR^(a)-alkylene-NR^(a)R^(b); or

in Y², R¹¹ is H, halogen, hydroxyl or alkyl;

in Y², ring C is a monocyclic, bicyclic, or tricyclic 5- to 12-memberedheterocycle containing at least one atom selected from N, O, or S,wherein ring C is optionally substituted with R¹⁵;

R^(a) and R^(b) are each independently, H or alkyl;

R^(c) is H, alkyl, -alkyl-NR^(a)R^(b), or heterocyclyl;

R^(d) is alkyl, -alkyl-NR^(a)R^(b), or heterocyclyl;

wherein hetercocycyl in R¹¹, R¹², R¹³, R^(c), and R^(d) is eachindependently optionally substituted with R¹⁵;

R¹⁵ is halogen, hydroxyl, alkyl, alkylhydroxyl, oxo, —C(O)-alkyl,—C(O)OR^(a); —NR^(a)C(O)-alkyl, —(CH₂)_(n)—C(O)NR^(a)R^(b),—NR^(a)R^(b); or —S(O)_(n)-alkyl,

n is 0, 1, or 2; and

m is 0, 1, or 2;

wherein the compound is not

In embodiments, Z² is N and Z¹, Z³, and Z⁴ are each independently C orCR⁸.

In embodiments, Z¹ is N and Z², Z³, and Z⁴ are each independently C orCR⁸.

In embodiments, Z¹ and Z³ are each N, and Z² and Z⁴ are eachindependently C or CR⁸.

In embodiments, Z¹ and Z⁴ are each N, and Z³ and Z⁴ are eachindependently C or CR⁸.

In embodiments, the compound of formula (I) has the structure has astructure according to formula (II)

or a pharmaceutically acceptable salt or solvate thereof.

In embodiments, W is —S(O)₂R⁹.

In embodiments, R⁹ is C₁-C₆ alkyl or C₃-C₆ alkyl, each optionallysubstituted.

In embodiments, L is a bond.

In embodiments, the compound of formula (I) has the structure accordingto formula (III)

In embodiments, R² and R³ are each H or C₁-C₃ alkyl.

In embodiments, R⁴ and R⁵ are each H.

In embodiments, R⁶ and R⁷ are each independently H or halogen.

In embodiments, R⁶ and R³ together forms a saturated, unsaturated, orpartially saturated, 5- or 6-membered ring.

In embodiments, R⁶ and R³ together forms a saturated 5-membered ring.

In embodiments, R¹⁰ and R¹⁴ are each H.

In embodiments, at least one of R¹¹ and R¹³ is a halogen.

In embodiments, Y is Y¹.

In embodiments, one of R¹¹, R¹² and R¹³ is an optionally substitutedheterocyclyl.

In embodiments, the heterocyclyl is selected from piperidine,piperazine, hexahydropyrimidine, morpholine, tetrahydropyran, thiane, orthiomorpholine, each optionally substituted.

In embodiments, the heterocyclyl is a bicycle.

In embodiments, the heterocyclyl is selected from

each of which is optionally substituted with R¹⁵.

In embodiments, one of R¹¹, R¹² and R¹³ is —(CH₂)_(n)—C(O)NR^(a)R^(c),—(CH₂)_(n)—NR^(a)C(O)R^(d), —(CH₂)_(n)—C(O)(CH₂)_(n)—, —NR^(a)R^(b),—NR^(a)-alkylene-NR^(a)R^(b), or—(CH₂)_(n)—C(O)NR^(a)-alkylene-NR^(a)R^(b).

In embodiments, one of R¹¹, R¹² and R¹³ is —NR^(a)-alkylene-NR^(a)R^(b)or —(CH₂)_(n)—C(O)NR^(a)-alkylene-NR^(a)R^(b).

In embodiments, wherein Y is Y².

In embodiments, Y² is selected from:

each of which is optionally substituted with R¹⁵; and R¹⁶ is H or C₁-C₃alkyl.

In embodiments, R⁹ is C₁-C₆ alkyl or C₃-C₆ alkyl, each optionallysubstituted.

In embodiments, the compound of formula (I) has the structure accordingto formula (IV)

or a pharmaceutically acceptable salt or solvate thereof.

In embodiments, W is —S(O)₂R⁹.

In embodiments, R⁹ is C₁-C₆ alkyl or C₃-C₆ alkyl, each optionallysubstituted.

In embodiments, L is a bond.

In embodiments, the compound of formula (I) has the structure has astructure according to formula (V)

or a pharmaceutically acceptable salt or solvate thereof.

In embodiments, R² and R³ are each H or C₁-C₃ alkyl. In embodiments, R⁴and R⁵ are each H. In embodiments, R⁶ and R⁷ are each independently H orhalogen. In embodiments, R¹⁰ and R¹⁴ are each H.

In embodiments, at least one of R¹¹ and R¹³ is a halogen. Inembodiments, Y is Y. In embodiments, one of R¹¹, R¹² and R¹³ is anoptionally substituted heterocyclyl. In embodiments, the heterocyclyl isselected from piperidine, piperazine, hexahydropyrimidine, morpholine,tetrahydropyran, thiane, or thiomorpholine, each optionally substituted.In embodiments, the heterocyclyl is a bicycle.

In embodiments, the heterocyclyl is selected from

each of which is optionally substituted with R¹⁵.

In embodiments, one of R11, R12 and R13 is —(CH2)n-C(O)NRaRc,—(CH2)n-NRaC(O)Rd, —(CH2)n-C(O)(CH2)n-, —NRaRb, —NRa-alkylene-NRaRb, or—(CH2)n-C(O)NRa-alkylene-NRaRb;

In embodiments, one of R11, R12 and R13 is —NRa-alkylene-NRaRb or—(CH2)n-C(O)NRa-alkylene-NRaRb.

In embodiments, Y is Y2. In embodiments, Y² is selected from:

each of which is optionally substituted with R¹⁵; andR¹⁶ is H or C₁-C₃ alkyl.

In embodiments, the disclosure provides for a compound according toformula (X′):

or a pharmaceutically acceptable salt or solvate thereof;wherein:

Ring A is 5- or 6-membered ring selected from heteroaryl, heterocyclyl,aryl, or carbocylyl;

ring A and ring B are each aromatic;

V is

L is a bond or —CH₂—;

W is —S(O)_(m)R⁹, —P(O)₂R⁹, or —P(═S)₂R⁹;

R², R^(2a) and R³ are each independently H or alkyl;

R⁴ and R⁵ are each independently H, halogen, hydroxyl or alkyl;

R⁶ and R⁷ are each independently H, halogen, hydroxyl or alkyl; or

alternatively, R⁶ and R³ together or R⁷ and R³ together forms asaturated, unsaturated, or partially saturated, 5- or 6-membered ring;

R⁸ is H, halogen, or alkyl;

R⁹ is alkyl, cycloalkyl, or aryl, wherein cycloalkyl and aryl isoptionally substituted with one or more of halogen or alkyl;

Y is selected from

-M-carbocyclyl (Y⁵), or -M-heterocyclyl (Y⁶);

in Y¹ and Y², R¹⁰ and R¹⁴ are each independently H, halogen, hydroxyl oralkyl;

in Y¹, R¹¹, R¹² and R¹³ are each independently H, halogen, alkyl,alkoxy, heterocyclyl, —(CH₂)_(n)—C(O)NR^(a)R^(c),—(CH₂)_(n)—NR^(a)C(O)R^(d), —(CH₂)_(n)—C(O)(CH₂)_(n)—, —NR^(a)R^(b),—NR^(a)-alkylene-NR^(a)R^(b) or—(CH₂)_(n)—C(O)NR^(a)-alkylene-NR^(a)R^(b); or

in Y², R¹¹ is H, halogen, hydroxyl or alkyl;

in Y², ring C is a monocyclic, bicyclic, or tricyclic 5- to 12-memberedheterocycle containing at least one atom selected from N, O, or S,wherein ring C is optionally substituted with R¹⁵;

in Y⁵, carbocycle is monocyclic or bicyclic ring, optionally substitutedwith one or more R²⁰;

in Y⁶, heterocycle is monocyclic or bicyclic ring containing at leastone atom selected from O, S, or N, optionally substituted with one ormore R²⁰;

R²⁰ is each H, halogen, hydroxyl, alkyl, or oxo CN, —C(O)NR^(a)R^(b),aralykyl, aryl, heteroaralkyl, heteroaryl;

in Y⁵ and Y⁶, M is a bond or —CH₂—;

R^(a) and R^(b) are each independently, H or alkyl;

R^(c) is H, alkyl, -alkyl-NR^(a)R^(b), or heterocyclyl;

R^(d) is alkyl, -alkyl-NR^(a)R^(b), or heterocyclyl;

wherein hetercocycyl in R¹¹, R¹², R¹³, R^(c), and R^(d) is eachindependently optionally substituted with R¹⁵;

R¹⁵ is halogen, hydroxyl, alkyl, alkylhydroxyl, oxo, —C(O)-alkyl,—C(O)OR^(a); —NR^(a)C(O)-alkyl, —(CH₂)_(n)—C(O)NR^(a)R^(b),—NR^(a)R^(b); or —S(O)_(n)-alkyl,

n is 0, 1, or 2; and

m is 0, 1, or 2.

In embodiments, the compound has a structure according to formula (X):

or a pharmaceutically acceptable salt or solvate thereof;wherein:

Z¹, Z² and Z³ are each S, N or CR⁸, provided that at least one of Z¹, Z²or Z³ is N or S and at most two of Z¹, Z² or Z³ is N or S;

ring A and ring B are each aromatic;

V is

L is a bond or —CH₂—;

W is —S(O)_(m)R⁹, —P(O)₂R⁹, or —P(═S)₂R⁹;

R², R^(2a) and R³ are each independently H or alkyl;

R⁴ and R⁵ are each independently H, halogen, hydroxyl or alkyl;

R⁶ and R⁷ are each independently H, halogen, hydroxyl or alkyl; or

alternatively, R⁶ and R³ together or R⁷ and R³ together forms asaturated, unsaturated, or partially saturated, 5- or 6-membered ring;

R⁸ is H, halogen, or alkyl;

R⁹ is alkyl, cycloalkyl, or aryl, wherein cycloalkyl and aryl isoptionally substituted with one or more of halogen or alkyl;

Y is selected from

in Y¹ and Y², R¹⁰ and R¹⁴ are each independently H, halogen, hydroxyl oralkyl;

in Y¹, R¹¹, R¹² and R¹³ are each independently H, halogen, alkyl,alkoxy, heterocyclyl, —(CH₂)_(n)—C(O)NR^(a)R^(c),—(CH₂)_(n)—NR^(a)C(O)R^(d), —(CH₂)_(n)—C(O)(CH₂)_(n)—, —NR^(a)R^(b),—NR^(a)-alkylene-NR^(a)R^(b) or—(CH₂)_(n)—C(O)NR^(a)-alkylene-NR^(a)R^(b); or

in Y², R¹¹ is H, halogen, hydroxyl or alkyl;

in Y², ring C is a monocyclic, bicyclic, or tricyclic 5- to 12-memberedheterocycle containing at least one atom selected from N, O, or S,wherein ring C is optionally substituted with R¹⁵;

in Y³, R¹⁰, R¹¹, R¹³ and R¹⁴ are each H, halogen, hydroxyl or alkyl;

in Y³, R¹⁶ is H or alkyl;

in Y⁴, R¹⁰, R¹³ and R¹⁴ are each H, halogen, hydroxyl or alkyl;

in Y⁴, Z⁴ is NR^(a) or O;

in Y³ and Y⁴, M is a bond or —CH₂—;

R^(a) and R^(b) are each independently, H or alkyl;

R^(c) is H, alkyl, -alkyl-NR^(a)R^(b), or heterocyclyl;

R^(d) is alkyl, -alkyl-NR^(a)R^(b), or heterocyclyl;

wherein hetercocycyl in R¹¹, R¹², R¹³, R^(c), and R^(d) is eachindependently optionally substituted with R¹⁵;

R¹⁵ is halogen, hydroxyl, alkyl, alkylhydroxyl, oxo, —C(O)-alkyl,—C(O)OR^(a); —NR^(a)C(O)-alkyl, —(CH₂)_(n)—C(O)NR^(a)R^(b),—NR^(a)R^(b); or —S(O)_(n)-alkyl,

n is 0, 1, or 2; and

m is 0, 1, or 2.

In embodiments, Z¹, Z² and Z³ are each S or CR⁸, wherein exactly one ofZ¹, Z² or Z³ is S.

In embodiments, Z¹ is S.

In embodiments, Z³ is S.

In embodiments, V is V².

In embodiments, R^(2a) is H and R³ is alkyl.

In embodiments, R^(2a) is H and R³ is C₃-C₆ cycloalkyl.

In embodiments, V is

In embodiments, V is V¹.

In embodiments, W is —S(O)₂R⁹.

In embodiments, R⁹ is C₁-C₆ alkyl or C₃-C₆ alkyl, each optionallysubstituted.

In embodiments, L is a bond.

In embodiments, R⁴ and R⁵ are each H.

In embodiments, R⁶ and R⁷ are each independently H or halogen.

In embodiments, R⁶ and R³ together forms a saturated, unsaturated, orpartially saturated, 5- or 6-membered ring.

In embodiments, R⁶ and R³ together forms a saturated 5-membered ring.

In embodiments, Y is Y¹.

In embodiments, one of R¹¹, R¹² and R¹³ is an optionally substitutedheterocyclyl.

In embodiments, the heterocyclyl is selected from piperidine,piperazine, hexahydropyrimidine, morpholine, tetrahydropyran, thiane, orthiomorpholine, each optionally substituted.

In embodiments, the heterocyclyl is a bicycle.

In embodiments, the heterocyclyl is selected from

each of which is optionally substituted with R⁵.

In embodiments, one of R¹¹, R¹² and R¹³ is —(CH₂)_(n)—C(O)NR^(a)R^(c),—(CH₂)_(n)—NR^(a)C(O)R_(d), —(CH₂)_(n)—C(O)(CH₂)_(n)—, —NR^(a)R^(b),—NR^(a)-alkylene-NR^(a)R^(b), or—(CH₂)_(n)—C(O)NR^(a)-alkylene-NR^(a)R^(b).

In embodiments, one of R¹¹, R¹² and R¹³ is —NR^(a)-alkylene-NR^(a)R^(b)or —(CH₂)_(n)—C(O)NR^(a)-alkylene-NR^(a)R^(b).

In embodiments, Y is Y².

In embodiments, Y² is selected from:

each of which is optionally substituted with R¹⁵; and R¹⁶ is H or C₁-C₃alkyl.

In embodiments, Y is Y³.

In embodiments, R¹⁰, R¹¹, R¹³ and R¹⁴ are each H.

In embodiments, R¹⁶ is H or methyl.

In embodiments, M is —CH₂—.

In embodiments, wherein Y is Y⁴.

In embodiments, R¹⁰, R¹³ and R¹⁴ are each H.

In embodiments, Z⁴ is NH or NCH₃.

In embodiments, the compound is selected from:

or a pharmaceutically acceptable salt or solvate thereof.

In embodiments, the compound is

or a pharmaceutically acceptable salt or solvate thereof.

In embodiments, compounds disclosed herein have a BRD4-inhibitingactivity corresponding to an IC50 of about 20 μM or less, 10 μM or less,about 5 μM or less, about 1 μM or less, or about 0.1 μM or less. In someembodiments, the compounds with a BRD4-inhibiting activity correspondingto an IC50 of about 0.1 μM or less may have a structure according toformula (IV).

In some embodiments, the compounds with a BRD4-inhibiting activitycorresponding to an IC50 of about 0.1 μM or less may include thecompounds of Table 1:

TABLE 1 BRD4 IC50 Structure (μM)

0.094

0.063

0.094

0.006

In some embodiments, the compounds of the present disclosure exhibitBRD4-inhibitory activity, but are inactive against or show negligibleinhibition against JAK2 tyrosine kinase. In such embodiments, thecompounds may include the compounds of Table 2.

TABLE 2 Structure BRD4 IC50 (μM)

0.094

0.388

1.2

1.7

0.16

1.0

3.2

2.6

0.450

0.399

In embodiments, compounds disclosed herein have a JAK2 tyrosine kinaseinhibiting activity corresponding to an IC50 of about 5 μM or less,about 1.0 μM or less, about 0.1 μM or less, about 0.01 μM or less, about0.005 μM or less, or less or about 0.001 μM or less. In someembodiments, the compounds with a JAK2 tyrosine kinase inhibitingactivity corresponding to an IC50 of about 0.005 μM or less may have astructure according to formula (III).

In specific embodiments, the compound with a JAK2 tyrosine kinaseinhibiting activity corresponding to an IC50 of about 0.005 μM or lessmay include at least one of the following compounds of Table 3:

TABLE 3 JAK2 IC50 Structure (μM)

0.0025

0.003

0.002

0.0043

0.0044

0.0048

0.003

0.005

In other specific embodiments, the compounds having a JAK2 tyrosinekinase inhibiting activity corresponding to an IC50 of about 0.001 μM orless may include the compounds of Table 4.

TABLE 4 Structure JAK2 IC50 (μM)

0.0007 μM

0.00018 μM

0.0006 μM

In embodiments, compounds disclosed herein have a BRD4-inhibitingactivity corresponding to an IC50 of about 10 μM or less and a JAK2tyrosine kinase inhibiting activity corresponding to an IC50 of about1.0 μM or less, or a BRD4-inhibiting activity corresponding to an IC50of about 5 μM or less and a JAK2 tyrosine kinase inhibiting activitycorresponding to an IC50 of about 0.1 μM or less, or a BRD4-inhibitingactivity corresponding to an IC50 of about 1 μM or less about a JAK2tyrosine kinase inhibiting activity corresponding to an IC50 of 0.01 orless. In some embodiments, the compounds having a BRD4-inhibitingactivity corresponding to an IC50 of about 1.0 μM or less and a JAK2tyrosine kinase inhibiting activity corresponding to an IC50 of about0.005 μM or less may have a structure according to formula (VI):

wherein:

R⁹ is alkyl, cycloalkyl, or aryl, wherein cycloalkyl and aryl isoptionally substituted with one or more of halogen or alkyl; and

R¹² and R¹³ are each independently H, halogen, alkyl, heterocyclyl,—(CH₂)_(n)—C(O)NR^(a)R^(c), —(CH₂)_(n)—NR^(a)C(O)R^(d),—(CH₂)_(n)—C(O)(CH₂)_(n)—, —NR^(a)R^(b), —NR^(a)-alkylene-NR^(a)R^(b),or —(CH₂)_(n)—C(O)NR^(a)-alkylene-NR^(a)R^(b).

R^(a) and R^(b) are each independently, H or alkyl;

R^(c) is H, alkyl, -alkyl-NR^(a)R^(b), or heterocyclyl;

R^(d) is alkyl, -alkyl-NR^(a)R^(b), or heterocyclyl; and

wherein:

hetercocycyl in R¹², R^(c), and R^(d) is each independently optionallysubstituted with R¹⁵;

R¹⁵ is halogen, hydroxyl, alkyl, alkylhydroxyl, oxo, —C(O)-alkyl,—C(O)OR^(a); —NR^(a)C(O)-alkyl, —(CH₂)_(n)—C(O)NR^(a)R^(b),—NR^(a)R^(b); or —S(O)_(n)-alkyl,

n is 0, 1, or 2; and

m is 0, 1, or 2.

In specific embodiments, the compounds having a BRD4-inhibiting activitycorresponding to an IC50 of 1.0 LM or less and with a JAK2 tyrosinekinase inhibiting activity corresponding to an IC50 of 0.005 μM or lessmay include compounds of Table 5.

TABLE 5 BRD4 JAK2 IC50 IC50 Structure (μM) (μM)

0.22 0.0074

0.355 0.0025

0.173 0.0073

0.131 0.003

In embodiments, the compound of the present disclosure may be selectedfrom one or more of the compounds from Table 6 appended hereto.

Pharmaceutical Compositions and Formulations

In embodiments, the present disclosure provides for pharmaceuticalcompositions which inhibit the activity of at least one bromodomain,such as a bromodomain on BRDT, BRD2, BRD3, or BRD4. In embodiments, thepresent disclosure provides for pharmaceutical compositions whichinhibit the activity of at least one Janus kinase, such JAK1, JAK2, orJAK3. In embodiments, the present disclosure provides for pharmaceuticalcompositions which inhibit the activity at least one bromodomain and theactivity of at least one Janus Kinase. In particular embodiments, thepharmaceutical compositions of the present disclosure inhibit theactivity of BRD4 and the activity of JAK2 tyrosine kinase.

In one embodiment, a pharmaceutical composition comprises one or morecompounds of formula (I′) (I), (II), (III), (IV), (V), (VI), (X′), or(X), or a pharmaceutically acceptable salt or solvate thereof. In someembodiments, one or more of the compounds of formula (I′) (I), (II),(III), (IV), (V), (VI), (X′), or (X), or a pharmaceutically acceptablesalt or solvate thereof inhibits the activity at least one bromodomain,such as a bromodomain on BRDT, BRD2, BRD3, or BRD4. In otherembodiments, one or more of the compounds of formula (I′) (I), (II),(III), (IV), (V), (VI), (X′), or (X), or a pharmaceutically acceptablesalt or solvate thereof inhibits the activity of a at least one Janustyrosine kinase. In another embodiment, the or more of the compounds offormula (I′) (I), (II), (III), (IV), (V), (VI), (X′), or (X), or apharmaceutically acceptable salt or solvate thereof is a dual inhibitorof BRD4 activity and of JAK2 tyrosine kinase activity.

In one embodiment of the present disclosure, a pharmaceuticalcomposition comprises a therapeutically effective amount of one or morecompounds of formula (I′) (I), (II), (III), (IV), (V), (VI), (X′), or(X), or a pharmaceutically acceptable salt or solvate thereof.

In a specific embodiment, a pharmaceutical composition, as describedherein, comprises one or more compounds selected from Table 1, or apharmaceutically acceptable salt or solvate thereof. In another specificembodiment, a pharmaceutical composition as described herein compriseone or more compounds selected from Table 2, or a pharmaceuticallyacceptable salt or solvate thereof. In yet another specific embodiment,a pharmaceutical composition as described herein comprise one or morecompounds selected from Table 3, or a pharmaceutically acceptable saltor solvate thereof. In still another specific embodiment, apharmaceutical composition as described herein comprise one or morecompounds selected from Table 4, or a pharmaceutically acceptable saltor solvate thereof. In still another specific embodiment, apharmaceutical composition as described herein comprise one or morecompounds selected from Table 5, or a pharmaceutically acceptable saltor solvate thereof. In another specific embodiment, a pharmaceuticalcomposition as described herein comprise one or more compounds selectedfrom Table 6, or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, a pharmaceutical composition described herein doesnot contain:

In one embodiment, a pharmaceutical composition, as described herein,comprising one or more compounds of formula ((I′) (I), (II), (III),(IV), (V), (VI), (X′), or (X), or a pharmaceutically acceptable salt orsolvate thereof, further comprises one or more additionaltherapeutically active agents. In one embodiment, one or more additionaltherapeutically active agents are selected from therapeutics useful fortreating cancer.

In a further embodiment of the present disclosure, a pharmaceuticalcomposition comprising one or more compounds of formula (I′) (I), (II),(III), (IV), (V), (VI), (X′), or (X), or a pharmaceutically acceptablesalt or solvate thereof, and a pharmaceutically acceptable excipient oradjuvant is provided. The pharmaceutically acceptable excipients andadjuvants are added to the composition or formulation for a variety ofpurposes. In another embodiment, a pharmaceutical composition comprisingone or more compounds of formula (I′) (I), (II), (III), (IV), (V), (VI),(X′), or (X), or a pharmaceutically acceptable salt or solvate thereof,further comprises a pharmaceutically acceptable carrier. In oneembodiment, a pharmaceutically acceptable carrier includes apharmaceutically acceptable excipient, binder, and/or diluent. In oneembodiment, suitable pharmaceutically acceptable excipients include, butare not limited to, water, salt solutions, alcohol, polyethyleneglycols, gelatin, lactose, amylase, magnesium stearate, talc, silicicacid, viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone.

In certain embodiments, the pharmaceutical compositions of the presentdisclosure may additionally contain other adjunct componentsconventionally found in pharmaceutical compositions, at theirart-established usage levels. Thus, for example, the pharmaceuticalcompositions may contain additional, compatible, pharmaceutically-activematerials such as, for example, antipruritics, astringents, localanesthetics or anti-inflammatory agents, or may contain additionalmaterials useful in physically formulating various dosage forms of thecompositions of the present invention, such as dyes, flavoring agents,preservatives, antioxidants, opacifiers, thickening agents andstabilizers. However, such materials, when added, should not undulyinterfere with the biological activities of the components of thecompositions of the present invention. The formulations can besterilized and, if desired, mixed with auxiliary agents, e.g.,lubricants, preservatives, stabilizers, wetting agents, emulsifiers,salts for influencing osmotic pressure, buffers, colorings, flavoringsand/or aromatic substances and the like which do not deleteriouslyinteract with the oligonucleotide(s) of the formulation.

For the purposes of this disclosure, the compounds of the presentdisclosure can be formulated for administration by a variety of meansincluding orally, parenterally, by inhalation spray, topically, orrectally in formulations containing pharmaceutically acceptablecarriers, adjuvants and vehicles. The term parenteral as used hereincludes subcutaneous, intravenous, intramuscular, and intraarterialinjections with a variety of infusion techniques. Intraarterial andintravenous injection as used herein includes administration throughcatheters.

The compounds disclosed herein can be formulated in accordance with theroutine procedures adapted for desired administration route.Accordingly, the compounds disclosed herein can take such forms assuspensions, solutions or emulsions in oily or aqueous vehicles, and cancontain formulatory agents such as suspending, stabilizing and/ordispersing agents. The compounds disclosed herein can also be formulatedas a preparation for implantation or injection. Thus, for example, thecompounds can be formulated with suitable polymeric or hydrophobicmaterials (e.g., as an emulsion in an acceptable oil) or ion exchangeresins, or as sparingly soluble derivatives (e.g., as a sparinglysoluble salt). Alternatively, the active ingredient can be in powderform for constitution with a suitable vehicle, e.g., sterilepyrogen-free water, before use. Suitable formulations for each of thesemethods of administration can be found, for example, in Remington: TheScience and Practice of Pharmacy, A. Gennaro, ed., 20th edition,Lippincott, Williams & Wilkins, Philadelphia, Pa.

In certain embodiments, a pharmaceutical composition of the presentdisclosure is prepared using known techniques, including, but notlimited to mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or tableting processes.

In one embodiment, the present disclosure provides a pharmaceuticalcomposition comprising a compound of formula (I′) (I), (II), (III),(IV), (V), (VI), (X′), or (X), or a pharmaceutically acceptable salt orsolvate thereof, as disclosed herein, combined with a pharmaceuticallyacceptable carrier. In one embodiment, suitable pharmaceuticallyacceptable carriers include, but are not limited to, inert solid fillersor diluents and sterile aqueous or organic solutions. Pharmaceuticallyacceptable carriers are well known to those skilled in the art andinclude, but are not limited to, from about 0.01 to about 0.1 μM andpreferably 0.05 μM phosphate buffer or 0.8% saline. Suchpharmaceutically acceptable carriers can be aqueous or non-aqueoussolutions, suspensions and emulsions. Examples of non-aqueous solventssuitable for use in the present application include, but are not limitedto, propylene glycol, polyethylene glycol, vegetable oils such as oliveoil, and injectable organic esters such as ethyl oleate.

Aqueous carriers suitable for use in the present application include,but are not limited to, water, ethanol, alcoholic/aqueous solutions,glycerol, emulsions or suspensions, including saline and buffered media.Oral carriers can be elixirs, syrups, capsules, tablets and the like.

Liquid carriers suitable for use in the present application can be usedin preparing solutions, suspensions, emulsions, syrups, elixirs andpressurized compounds. The active ingredient can be dissolved orsuspended in a pharmaceutically acceptable liquid carrier such as water,an organic solvent, a mixture of both or pharmaceutically acceptableoils or fats. The liquid carrier can contain other suitablepharmaceutical additives such as solubilizers, emulsifiers, buffers,preservatives, sweeteners, flavoring agents, suspending agents,thickening agents, colors, viscosity regulators, stabilizers orosmo-regulators.

Liquid carriers suitable for use in the present application include, butare not limited to, water (partially containing additives as above, e.g.cellulose derivatives, preferably sodium carboxymethyl cellulosesolution), alcohols (including monohydric alcohols and polyhydricalcohols, e.g. glycols) and their derivatives, and oils (e.g.fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can also include an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are useful insterile liquid form comprising compounds for parenteral administration.The liquid carrier for pressurized compounds disclosed herein can behalogenated hydrocarbon or other pharmaceutically acceptable propellent.

Solid carriers suitable for use in the present application include, butare not limited to, inert substances such as lactose, starch, glucose,methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol andthe like. A solid carrier can further include one or more substancesacting as flavoring agents, lubricants, solubilizers, suspending agents,fillers, glidants, compression aids, binders or tablet-disintegratingagents; it can also be an encapsulating material. In powders, thecarrier can be a finely divided solid which is in admixture with thefinely divided active compound. In tablets, the active compound is mixedwith a carrier having the necessary compression properties in suitableproportions and compacted in the shape and size desired. The powders andtablets preferably contain up to 99% of the active compound. Suitablesolid carriers include, for example, calcium phosphate, magnesiumstearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins. Atablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in a freeflowing form such as a powder or granules, optionally mixed with abinder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (e.g., sodiumstarch glycolate, cross-linked povidone, cross-linked sodiumcarboxymethyl cellulose) surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered compound moistened with an inert liquid diluent. The tabletsmay optionally be coated or scored and may be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropyl methylcellulose in varying proportionsto provide the desired release profile. Tablets may optionally beprovided with an enteric coating, to provide release in parts of the gutother than the stomach.

Parenteral carriers suitable for use in the present application include,but are not limited to, sodium chloride solution, Ringer's dextrose,dextrose and sodium chloride, lactated Ringer's and fixed oils.Intravenous carriers include fluid and nutrient replenishers,electrolyte replenishers such as those based on Ringer's dextrose andthe like. Preservatives and other additives can also be present, suchas, for example, antimicrobials, antioxidants, chelating agents, inertgases and the like.

Carriers suitable for use in the present application can be mixed asneeded with disintegrants, diluents, granulating agents, lubricants,binders and the like using conventional techniques known in the art. Thecarriers can also be sterilized using methods that do not deleteriouslyreact with the compounds, as is generally known in the art.

Diluents may be added to the formulations of the present invention.Diluents increase the bulk of a solid pharmaceutical composition and/orcombination, and may make a pharmaceutical dosage form containing thecomposition and/or combination easier for the patient and care giver tohandle. Diluents for solid compositions and/or combinations include, forexample, microcrystalline cellulose (e.g., AVICEL), microfine cellulose,lactose, starch, pregelatinized starch, calcium carbonate, calciumsulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphatedihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate,magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g.,EUDRAGIT®), potassium chloride, powdered cellulose, sodium chloride,sorbitol, and talc.

Additional embodiments relate to the pharmaceutical formulations whereinthe formulation is selected from the group consisting of a solid,powder, liquid and a gel. In certain embodiments, a pharmaceuticalcomposition of the present invention is a solid (e.g., a powder, tablet,a capsule, granulates, and/or aggregates). In certain of suchembodiments, a solid pharmaceutical composition comprising one or moreingredients known in the art, including, but not limited to, starches,sugars, diluents, granulating agents, lubricants, binders, anddisintegrating agents.

Solid pharmaceutical compositions that are compacted into a dosage form,such as a tablet, may include excipients whose functions include helpingto bind the active ingredient and other excipients together aftercompression. Binders for solid pharmaceutical compositions and/orcombinations include acacia, alginic acid, carbomer (e.g., carbopol),carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guargum, gum tragacanth, hydrogenated vegetable oil, hydroxyethyl cellulose,hydroxypropyl cellulose (e.g., KLUCEL), hydroxypropyl methyl cellulose(e.g., METHOCEL), liquid glucose, magnesium aluminum silicate,maltodextrin, methylcellulose, polymethacrylates, povidone (e.g.,KOLLIDON, PLASDONE), pregelatinized starch, sodium alginate, and starch.

The dissolution rate of a compacted solid pharmaceutical composition inthe patient's stomach may be increased by the addition of a disintegrantto the composition and/or combination. Disintegrants include alginicacid, carboxymethylcellulose calcium, carboxymethylcellulose sodium(e.g., AC-DI-SOL and PRIMELLOSE), colloidal silicon dioxide,croscarmellose sodium, crospovidone (e.g., KOLLIDON and POLYPLASDONE),guar gum, magnesium aluminum silicate, methyl cellulose,microcrystalline cellulose, polacrilin potassium, powdered cellulose,pregelatinized starch, sodium alginate, sodium starch glycolate (e.g.,EXPLOTAB), potato starch, and starch.

Glidants can be added to improve the flowability of a non-compactedsolid composition and/or combination and to improve the accuracy ofdosing. Excipients that may function as glidants include colloidalsilicon dioxide, magnesium trisilicate, powdered cellulose, starch,talc, and tribasic calcium phosphate.

When a dosage form such as a tablet is made by the compaction of apowdered composition, the composition is subjected to pressure from apunch and dye. Some excipients and active ingredients have a tendency toadhere to the surfaces of the punch and dye, which can cause the productto have pitting and other surface irregularities. A lubricant can beadded to the composition and/or combination to reduce adhesion and easethe release of the product from the dye. Lubricants include magnesiumstearate, calcium stearate, glyceryl monostearate, glycerylpalmitostearate, hydrogenated castor oil, hydrogenated vegetable oil,mineral oil, polyethylene glycol, sodium benzoate, sodium laurylsulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.

Flavoring agents and flavor enhancers make the dosage form morepalatable to the patient. Common flavoring agents and flavor enhancersfor pharmaceutical products that may be included in the compositionand/or combination of the present invention include maltol, vanillin,ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, andtartaric acid.

Solid and liquid compositions may also be dyed using anypharmaceutically acceptable colorant to improve their appearance and/orfacilitate patient identification of the product and unit dosage level.

In certain embodiments, a pharmaceutical composition of the presentinvention is a liquid (e.g., a suspension, elixir and/or solution). Incertain of such embodiments, a liquid pharmaceutical composition isprepared using ingredients known in the art, including, but not limitedto, water, glycols, oils, alcohols, flavoring agents, preservatives, andcoloring agents.

Liquid pharmaceutical compositions can be prepared using compounds offormula (I′) (I), (II), (III), (IV), (V), (VI), (X′), or (X), or apharmaceutically acceptable salt or solvate thereof, and any other solidexcipients where the components are dissolved or suspended in a liquidcarrier such as water, vegetable oil, alcohol, polyethylene glycol,propylene glycol, or glycerin.

For example, formulations for parenteral administration can contain ascommon excipients sterile water or saline, polyalkylene glycols such aspolyethylene glycol, oils of vegetable origin, hydrogenated naphthalenesand the like. In particular, biocompatible, biodegradable lactidepolymer, lactide/glycolide copolymer, orpolyoxyethylene-polyoxypropylene copolymers can be useful excipients tocontrol the release of active compounds. Other potentially usefulparenteral delivery systems include ethylene-vinyl acetate copolymerparticles, osmotic pumps, implantable infusion systems, and liposomes.Formulations for inhalation administration contain as excipients, forexample, lactose, or can be aqueous solutions containing, for example,polyoxyethylene-9-auryl ether, glycocholate and deoxycholate, or oilysolutions for administration in the form of nasal drops, or as a gel tobe applied intranasally. Formulations for parenteral administration canalso include glycocholate for buccal administration, methoxysalicylatefor rectal administration, or citric acid for vaginal administration.

Liquid pharmaceutical compositions can contain emulsifying agents todisperse uniformly throughout the composition and/or combination anactive ingredient or other excipient that is not soluble in the liquidcarrier. Emulsifying agents that may be useful in liquid compositionsand/or combinations of the present invention include, for example,gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus,pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetylalcohol.

Liquid pharmaceutical compositions can also contain a viscosityenhancing agent to improve the mouth-feel of the product and/or coat thelining of the gastrointestinal tract. Such agents include acacia,alginic acid bentonite, carbomer, carboxymethylcellulose calcium orsodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatinguar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylenecarbonate, propylene glycol alginate, sodium alginate, sodium starchglycolate, starch tragacanth, and xanthan gum.

Sweetening agents such as aspartame, lactose, sorbitol, saccharin,sodium saccharin, sucrose, aspartame, fructose, mannitol, and invertsugar may be added to improve the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate,butylated hydroxyl toluene, butylated hydroxyanisole, andethylenediamine tetraacetic acid may be added at levels safe foringestion to improve storage stability.

A liquid composition can also contain a buffer such as guconic acid,lactic acid, citric acid or acetic acid, sodium guconate, sodiumlactate, sodium citrate, or sodium acetate. Selection of excipients andthe amounts used may be readily determined by the formulation scientistbased upon experience and consideration of standard procedures andreference works in the field.

In one embodiment, a pharmaceutical composition is prepared foradministration by injection (e.g., intravenous, subcutaneous,intramuscular, etc.). In certain of such embodiments, a pharmaceuticalcomposition comprises a carrier and is formulated in aqueous solution,such as water or physiologically compatible buffers such as Hanks'ssolution, Ringer's solution, or physiological saline buffer. In certainembodiments, other ingredients are included (e.g., ingredients that aidin solubility or serve as preservatives). In certain embodiments,injectable suspensions are prepared using appropriate liquid carriers,suspending agents and the like. Certain pharmaceutical compositions forinjection are presented in unit dosage form, e.g., in ampoules or inmulti-dose containers. Certain pharmaceutical compositions for injectionare suspensions, solutions or emulsions in oily or aqueous vehicles, andmay contain formulatory agents such as suspending, stabilizing and/ordispersing agents. Certain solvents suitable for use in pharmaceuticalcompositions for injection include, but are not limited to, lipophilicsolvents and fatty oils, such as sesame oil, synthetic fatty acidesters, such as ethyl oleate or triglycerides, and liposomes. Aqueousinjection suspensions may contain substances that increase the viscosityof the suspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Optionally, such suspensions may also contain suitablestabilizers or agents that increase the solubility of the pharmaceuticalagents to allow for the preparation of highly concentrated solutions.

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, such as a solution in 1,3-butane-diol or prepared as alyophilized powder. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile fixed oils may conventionally be employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid may likewise be used in the preparationof injectables. Formulations for intravenous administration can comprisesolutions in sterile isotonic aqueous buffer. Where necessary, theformulations can also include a solubilizing agent and a localanesthetic to ease pain at the site of the injection. Generally, theingredients are supplied either separately or mixed together in unitdosage form, for example, as a dry lyophilized powder or water freeconcentrate in a hermetically sealed container such as an ampule orsachet indicating the quantity of active agent. Where the compound is tobe administered by infusion, it can be dispensed in a formulation withan infusion bottle containing sterile pharmaceutical grade water, salineor dextrose/water. Where the compound is administered by injection, anampule of sterile water for injection or saline can be provided so thatthe ingredients can be mixed prior to administration.

Suitable formulations further include aqueous and non-aqueous sterileinjection solutions that can contain antioxidants, buffers,bacteriostats, bactericidal antibiotics and solutes that render theformulation isotonic with the bodily fluids of the intended recipient;and aqueous and non-aqueous sterile suspensions, which can includesuspending agents and thickening agents.

In certain embodiments, a pharmaceutical composition of the presentinvention is formulated as a depot preparation. Certain such depotpreparations are typically longer acting than non-depot preparations. Incertain embodiments, such preparations are administered by implantation(for example subcutaneously or intramuscularly) or by intramuscularinjection. In certain embodiments, depot preparations are prepared usingsuitable polymeric or hydrophobic materials (for example an emulsion inan acceptable oil) or ion exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

In certain embodiments, a pharmaceutical composition of the presentinvention comprises a delivery system. Examples of delivery systemsinclude, but are not limited to, liposomes and emulsions. Certaindelivery systems are useful for preparing certain pharmaceuticalcompositions including those comprising hydrophobic compounds. Incertain embodiments, certain organic solvents such as dimethylsulfoxideare used.

In certain embodiments, a pharmaceutical composition of the presentinvention comprises a co-solvent system. Certain of such co-solventsystems comprise, for example, benzyl alcohol, a nonpolar surfactant, awater-miscible organic polymer, and an aqueous phase. In certainembodiments, such co-solvent systems are used for hydrophobic compounds.A non-limiting example of such a co-solvent system is the VPD co-solventsystem, which is a solution of absolute ethanol comprising 3% w/v benzylalcohol, 8% w/v of the nonpolar surfactant Polysorbate 80 and 65% w/vpolyethylene glycol 300. The proportions of such co-solvent systems maybe varied considerably without significantly altering their solubilityand toxicity characteristics. Furthermore, the identity of co-solventcomponents may be varied: for example, other surfactants may be usedinstead of Polysorbate 80; the fraction size of polyethylene glycol maybe varied; other biocompatible polymers may replace polyethylene glycol,e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides maysubstitute for dextrose.

In certain embodiments, a pharmaceutical composition of the presentinvention comprises a sustained-release system. A non-limiting exampleof such a sustained-release system is a semi-permeable matrix of solidhydrophobic polymers. In certain embodiments, sustained-release systemsmay, depending on their chemical nature, release pharmaceutical agentsover a period of hours, days, weeks or months.

Appropriate pharmaceutical compositions of the present disclosure can bedetermined according to any clinically-acceptable route ofadministration of the composition to the subject. The manner in whichthe composition is administered is dependent, in part, upon the causeand/or location. One skilled in the art will recognize the advantages ofcertain routes of administration. The method includes administering aneffective amount of the agent or compound (or composition comprising theagent or compound) to achieve a desired biological response, e.g., anamount effective to alleviate, ameliorate, or prevent, in whole or inpart, a symptom of a condition to be treated, e.g., oncology andneurology disorders. In various aspects, the route of administration issystemic, e.g., oral or by injection. The agents or compounds, orpharmaceutically acceptable salts or derivatives thereof, areadministered orally, nasally, transdermally, pulmonary, inhalationally,buccally, sublingually, intraperintoneally, subcutaneously,intramuscularly, intravenously, rectally, intrapleurally, intrathecally,intraportally, and parenterally. Alternatively or in addition, the routeof administration is local, e.g., topical, intra-tumor and peri-tumor.In some embodiments, the compound is administered orally.

In certain embodiments, a pharmaceutical composition of the presentdisclosure is prepared for oral administration. In certain of suchembodiments, a pharmaceutical composition is formulated by combining oneor more agents and pharmaceutically acceptable carriers. Certain of suchcarriers enable pharmaceutical compositions to be formulated as tablets,pills, dragees, capsules, liquids, gels, syrups, slurries, suspensionsand the like, for oral ingestion by a subject. Suitable excipientsinclude, but are not limited to, fillers, such as sugars, includinglactose, sucrose, mannitol, or sorbitol; cellulose preparations such as,for example, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone (PVP). In certain embodiments, such a mixture isoptionally ground and auxiliaries are optionally added. In certainembodiments, pharmaceutical compositions are formed to obtain tablets ordragee cores. In certain embodiments, disintegrating agents (e.g.,cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a saltthereof, such as sodium alginate) are added.

In certain embodiments, dragee cores are provided with coatings. Incertain such embodiments, concentrated sugar solutions may be used,which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquersolutions, and suitable organic solvents or solvent mixtures. Dyestuffsor pigments may be added to tablets or dragee coatings.

In certain embodiments, pharmaceutical compositions for oraladministration are push-fit capsules made of gelatin. Certain of suchpush-fit capsules comprise one or more pharmaceutical agents of thepresent invention in admixture with one or more filler such as lactose,binders such as starches, and/or lubricants such as talc or magnesiumstearate and, optionally, stabilizers. In certain embodiments,pharmaceutical compositions for oral administration are soft, sealedcapsules made of gelatin and a plasticizer, such as glycerol orsorbitol. In certain soft capsules, one or more pharmaceutical agents ofthe present invention are be dissolved or suspended in suitable liquids,such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Inaddition, stabilizers may be added.

In certain embodiments, pharmaceutical compositions are prepared forbuccal administration. Certain of such pharmaceutical compositions aretablets or lozenges formulated in conventional manner.

In certain embodiments, a pharmaceutical composition is prepared fortransmucosal administration. In certain of such embodiments penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art.

In certain embodiments, a pharmaceutical composition is prepared foradministration by inhalation. Certain of such pharmaceuticalcompositions for inhalation are prepared in the form of an aerosol sprayin a pressurized pack or a nebulizer. Certain of such pharmaceuticalcompositions comprise a propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In certain embodiments using a pressurized aerosol,the dosage unit may be determined with a valve that delivers a meteredamount. In certain embodiments, capsules and cartridges for use in aninhaler or insufflator may be formulated. Certain of such formulationscomprise a powder mixture of a pharmaceutical agent of the invention anda suitable powder base such as lactose or starch.

In other embodiments the compound of the present disclosure areadministered by the intravenous route. In further embodiments, theparenteral administration may be provided in a bolus or by infusion.

In certain embodiments, a pharmaceutical composition is prepared forrectal administration, such as a suppository or retention enema. Certainof such pharmaceutical compositions comprise known ingredients, such ascocoa butter and/or other glycerides.

In certain embodiments, a pharmaceutical composition is prepared fortopical administration. Certain of such pharmaceutical compositionscomprise bland moisturizing bases, such as ointments or creams.Exemplary suitable ointment bases include, but are not limited to,petrolatum, petrolatum plus volatile silicones, and lanolin and water inoil emulsions. Exemplary suitable cream bases include, but are notlimited to, cold cream and hydrophilic ointment.

In certain embodiments, the therapeutically effective amount issufficient to prevent, alleviate or ameliorate symptoms of a disease orto prolong the survival of the subject being treated. Determination of atherapeutically effective amount is well within the capability of thoseskilled in the art.

In certain embodiments, one or more compounds of formula (I′) (I), (II),(III), (IV), (V), (VI), (X′), or (X), or a pharmaceutically acceptablesalt or solvate thereof are formulated as a prodrug. In certainembodiments, upon in vivo administration, a prodrug is chemicallyconverted to the biologically, pharmaceutically or therapeutically moreactive form. In certain embodiments, prodrugs are useful because theyare easier to administer than the corresponding active form. Forexample, in certain instances, a prodrug may be more bioavailable (e.g.,through oral administration) than is the corresponding active form. Incertain instances, a prodrug may have improved solubility compared tothe corresponding active form. In certain embodiments, prodrugs are lesswater soluble than the corresponding active form. In certain instances,such prodrugs possess superior transmittal across cell membranes, wherewater solubility is detrimental to mobility. In certain embodiments, aprodrug is an ester. In certain such embodiments, the ester ismetabolically hydrolyzed to carboxylic acid upon administration. Incertain instances the carboxylic acid containing compound is thecorresponding active form. In certain embodiments, a prodrug comprises ashort peptide (polyaminoacid) bound to an acid group. In certain of suchembodiments, the peptide is cleaved upon administration to form thecorresponding active form.

In certain embodiments, a prodrug is produced by modifying apharmaceutically active compound such that the active compound will beregenerated upon in vivo administration. The prodrug can be designed toalter the metabolic stability or the transport characteristics of adrug, to mask side effects or toxicity, to improve the flavor of a drugor to alter other characteristics or properties of a drug. By virtue ofknowledge of pharmacodynamic processes and drug metabolism in vivo,those of skill in this art, once a pharmaceutically active compound isknown, can design prodrugs of the compound (see, e.g., Nogrady (1985)Medicinal Chemistry A Biochemical Approach, Oxford University Press, NewYork, pages 388-392).

In various aspects, the amount of the compound of formula (I′) (I),(II), (III), (IV), (V), (VI), (X′), and/or (X), or a pharmaceuticallyacceptable salt or solvate thereof, or compounds disclosed in Table 1,Table 2, Table 3, Table 4, Table 5, and/or Table 6, or apharmaceutically acceptable salt or solvate thereof, can be administeredat about 0.001 mg/kg to about 100 mg/kg body weight (e.g., about 0.01mg/kg to about 10 mg/kg or about 0.1 mg/kg to about 5 mg/kg).

The concentration of a disclosed compound in a pharmaceuticallyacceptable mixture will vary depending on several factors, including thedosage of the compound to be administered, the pharmacokineticcharacteristics of the compound(s) employed, and the route ofadministration. The agent may be administered in a single dose or inrepeat doses. The dosage regimen utilizing the compounds of the presentinvention is selected in accordance with a variety of factors includingtype, species, age, weight, sex and medical condition of the patient;the severity of the condition to be treated; the route ofadministration; the renal and hepatic function of the patient; and theparticular compound or salt thereof employed. Treatments may beadministered daily or more frequently depending upon a number offactors, including the overall health of a patient, and the formulationand route of administration of the selected compound(s). An ordinarilyskilled physician or veterinarian can readily determine and prescribethe effective amount of the drug required to prevent, counter or arrestthe progress of the condition.

The compounds or pharmaceutical compositions of the present disclosuremay be manufactured and/or administered in single or multiple unit doseforms.

Methods

The present disclosure relates to the use of one or more compoundsdisclosed herein, or a pharmaceutically acceptable salt thereof, whichcan inhibit the activity of at least one bromodomain, e.g., abromondomain on BRDT, BRD2, BRD3, or BRD4. The present disclosure alsorelates to the use of one or more compounds disclosed herein, or apharmaceutically acceptable salt thereof, which can inhibit the tyrosinekinase activity of at least one Janus kinase, e.g., JAK1, JAK2, or JAK3.Further, the present disclosure relates to the use of one or morecompounds disclosed herein, or a pharmaceutically acceptable saltthereof, which can inhibit the activity of at least one bromodomain(e.g., such as a bromondomain on BRDT, BRD2, BRD3, or BRD4) and thetyrosine kinase activity of at least one Janus kinase (e.g., JAK1, JAK2,or JAK).

More particularly, the present disclosure relates to the use of one ormore compounds of formula (I′) (I), (II), (III), (IV), (V), (VI), (X′),or (X), or a pharmaceutically acceptable salt or solvate thereof, whichcan inhibit BRD4 activity, JAK2 tyrosine kinase activity, or acombination thereof. In one embodiment, one or compounds of formula (I′)(I), (II), (III), (IV), (V), (VI), (X′), or (X), or a pharmaceuticallyacceptable salt or solvate thereof, which may inhibit both BRD4 activityand JAK2 tyrosine kinase activity.

In one embodiment, the compounds described herein may be used to treat acancer selected from one or more of the group consisting of bladdercancer, brain cancer, breast cancer, colorectal cancer, cervical cancer,gastrointestinal cancer, genitourinary cancer, head and neck cancer,lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renalcancer, skin cancer, and testicular cancer.

In another embodiment the cancer may be selected from one or more of thegroup consisting of Acute Lymphoblastic Leukemia, Acute MyeloidLeukemia, Adrenocortical Carcinoma, AIDS-Related Cancers, KaposiSarcoma, Lymphoma, Anal Cancer, Appendix Cancer, Astrocytomas, ChildhoodAtypical Teratoid/Rhabdoid Tumor, Basal Cell Carcinoma, Skin Cancer(Nonmelanoma), Childhood Bile Duct Cancer, Extrahepatic Bladder Cancer,Bone Cancer, Ewing Sarcoma Family of Tumors, Osteosarcoma and MalignantFibrous Histiocytoma, Brain Stem Glioma, Brain Tumors, Embryonal Tumors,Germ Cell Tumors, Craniopharyngioma, Ependymoma, Bronchial Tumors,Burkitt Lymphoma (Non-Hodgkin Lymphoma), Carcinoid Tumor,Gastrointestinal Carcinoma of Unknown Primary, Cardiac (Heart) Tumors,Lymphoma, Primary, Cervical Cancer, Childhood Cancers, Chordoma, ChronicLymphocytic Leukemia, Chronic Myelogenous Leukemia, ChronicMyeloproliferative Neoplasms Colon Cancer, Colorectal Cancer, CutaneousT-Cell Lymphoma, Ductal Carcinoma In Situ, Endometrial Cancer,Ependymoma, Esophageal Cancer, Esthesioneuroblastoma, Ewing Sarcoma,Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, ExtrahepaticBile Duct Cancer, Eye Cancer, Intraocular Melanoma, Retinoblastoma,Fibrous Histiocytoma of Bone, Malignant, and Osteosarcoma, GallbladderCancer, Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor,Gastrointestinal Stromal Tumors, Extragonadal Cancer, Ovarian Cancer,Testicular Cancer, Gestational Trophoblastic Disease, Glioma, Brain StemCancer, Hairy Cell Leukemia, Head and Neck Cancer, Heart Cancer,Hepatocellular (Liver) Cancer, Histiocytosis, Langerhans Cell Cancer,Hodgkin Lymphoma, Hypopharyngeal Cancer, Intraocular Melanoma, IsletCell Tumors, Pancreatic Neuroendocrine Tumors, Kaposi Sarcoma, KidneyCancer, Renal Cell Cancer, Wilms Tumor and Other Childhood KidneyTumors, Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia,Chronic Lymphocytic Cancer, Chronic Myelogenous Cancer, Hairy CellCancer, Lip and Oral Cavity Cancer, Liver Cancer (Primary), LobularCarcinoma In Situ (LCIS), Lung Cancer, Non-Small Cell Cancer, Small CellCancer, Lymphoma, Cutaneous T-Cell (Mycosis Fungoides and SézarySyndrome), Hodgkin Cancer, Non-Hodgkin Cancer, Macroglobulinemia,Waldenström, Male Breast Cancer, Malignant Fibrous Histiocytoma of Boneand Osteosarcoma, Melanoma, Intraocular (Eye) Cancer, Merkel CellCarcinoma, Mesothelioma, Malignant, Metastatic Squamous Neck Cancer withOccult Primary, Midline Tract Carcinoma Involving NUT Gene, MouthCancer, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma/PlasmaCell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndromes,Myelodysplastic/Myeloproliferative Neoplasms, Myelogenous Leukemia,Chronic, Myeloid Leukemia, Acute, Myeloma Multiple, ChronicMyeloproliferative Neoplasms, Nasal Cavity and Paranasal Sinus Cancer,Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non-SmallCell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Lip and OropharyngealCancer, Osteosarcoma and Malignant Fibrous Histiocytoma of Bone,Epithelial Cancer, Low Malignant Potential Tumor, Pancreatic Cancer,Pancreatic Neuroendocrine Tumors (Islet Cell Tumors), Papillomatosis,Paraganglioma, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer,Pheochromocytoma, Pituitary Tumor, Plasma Cell Neoplasm/MultipleMyeloma, Pleuropulmonary Blastoma, Primary Central Nervous SystemLymphoma, Rectal Cancer, Renal Cell (Kidney) Cancer, Retinoblastoma,Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma, Ewing Cancer, KaposiCancer, Osteosarcoma (Bone Cancer), Soft Tissue Cancer, Uterine Cancer,Sézary Syndrome, Skin Cancer, Childhood Melanoma, Merkel Cell Carcinoma,Nonmelanoma, Small Cell Lung Cancer, Small Intestine Cancer, Soft TissueSarcoma, Squamous Cell Carcinoma, Skin Cancer (Nonmelanoma), ChildhoodSquamous Neck Cancer with Occult Primary, Metastatic Cancer, Stomach(Gastric) Cancer, T-Cell Lymphoma, Cutaneous Cancer, Testicular Cancer,Throat Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer,Transitional Cell Cancer of the Renal Pelvis and Ureter, UnknownPrimary, Carcinoma of Childhood, Unusual Cancers of Childhood, UrethralCancer, Uterine Cancer, Endometrial Cancer, Uterine Sarcoma, VaginalCancer, Vulvar Cancer, Waldenström Macroglobulinemia, Wilms Tumor, andWomen's Cancers.

In a specific embodiment, the cancer is leukemia.

Having now generally described the invention, the same will be morereadily understood through reference to the following examples, whichare provided by way of illustration and are not intended to be limitingof the present invention.

All publications, patents and patent applications, including anydrawings and appendices therein are incorporated by reference in theirentirety for all purposes to the same extent as if each individualpublication, patent or patent application, drawing, or appendix wasspecifically and individually indicated to be incorporated by referencein its entirety for all purposes.

EXAMPLES Example 1: Bromodomain Binding and IC50 Calculation

An AlphaLisa assay was used to observe bromodomain binding and measureIC50s for the compounds disclosed herein. An AlphaLisa assay is abead-based assay used to detect interactions between bromodomains andpolyacetylated histone peptides. Donor and acceptor beads bound totarget and ligand are brought into proximity by this protein-proteininteraction. Excitation of the donor beads provokes the release ofsinglet oxygen that triggers a cascade of energy transfer reactions inthe acceptor beads, resulting in a sharp peak of light emission at 615nm.

Equipment Required

-   -   1. 384-well Optiplate from Perkin elmer (cat #6007299)    -   2. Plate centrifuge    -   3. Plate shaker    -   4. 96-well v-bottomed plates from Corning (Cat #3363)    -   5. Single channel and multi-channel pipettes    -   6. Microplate reader (Pherastar)

Stock and Final Assay Concentrations (FAC)

-   -   1. All reference and test compounds are made at a concentration        of 10 mM in DMSO. Compounds are serially diluted in DMSO and a        FAC starting from 10 μM to 10 point 3 fold serial dilutions is        arrived. FAC of DMSO is 1%.    -   2. Enzyme stock and FAC

Enzyme Stock concentration in μM FAC in nM BRD4-BD1 123.6 5 BRD4-BD291.1 20 BRD2-BD1 34.0 15 BRD3-BD! 23.8 8 BRDT-BD1 76.2 15

-   -   -   BRD4-BD1 GST tagged: BPS bioscience Cat: 31040        -   BRD4-BD2 GST tagged: BPS bioscience Cat: 31041        -   BRD2-BD1 GST tagged: BPS bioscience Cat: 31021        -   BRD3-BD1 GST tagged: BPS bioscience Cat: 31032        -   BRDT-BD1 GST tagged: BPS bioscience Cat: 31108

    -   3. Biotinylated substrate (Acetylated histone H4, biotinylated        substrate—cat no. AS64989-025, Anaspec) stock and FAC

Enzyme Sub-Stock concentration in μM FAC in nM BRD4-BD1 36.65 25BRD4-BD2 36.65 50 BRD2-BD1 36.65 50 BRD3-BD! 36.65 35 BRDT-BD1 36.65 50

-   -   4. Acceptor and donor beads stock and FAC

Stock concentration Working Stock Bead in mg/ml in μg/ml GlutathioneAcceptor 5 25 Streptavidin Donor 5 50

-   -   -   Glutathione Acceptor beads: Perkin Elmer Cat: AL109M        -   Streptavidin Donor beads: Perkin Elmer Cat: 6760002

    -   5. Buffers        -   For the enzyme and substrate dilution following buffer is            used (for 50 ml)        -   HEPES: 50 mM 2.5 ml        -   NaCl: 25 mM 1.25 ml        -   DTT: 10 mM 0.05 ml        -   BSA: 0.1% 0.05 g        -   MilliQ water: 45.7 ml        -   For dilution of acceptor and donor beads AlphaLISA 5X            epigenetics Buffer Perkin Elmer (Cat: AL008C) is used at 1×            concentration.

Procedure

-   -   1. Add 20 μl of the diluted compound to each well of the        384-well opti plate    -   2. Tap the plate gently    -   3. Add 10 μl of the enzyme to each well of the opti plate    -   4. Cover with plate sealer    -   5. Spin the plate briefly (640 rpm for 30 s) in a plate        centrifuge.    -   6. Incubate the plate at room temperature for 10 minutes    -   7. Add 10 μl of the substrate    -   8. Cover with plate sealer    -   9. Spin the plate briefly (640 rpm for 30 s) in a plate        centrifuge.    -   10. Cover with plate sealer and incubate at room temperature for        1 hour    -   11. After incubation, transfer 10 μl of reaction mix to fresh        wells of a 384-well plate.    -   12. Add 10 μl acceptor bead from working stock.    -   13. Cover with plate sealer    -   14. Spin the plate briefly (640 rpm for 30 s) in a plate        centrifuge.    -   15. Cover with plate sealer and incubate at room temperature for        30 minutes    -   16. Add 10 μl donor bead from working stock (in dark).    -   17. Cover with plate sealer    -   18. Spin the plate briefly (640 rpm for 30 s) in a plate        centrifuge.    -   19. Cover with plate sealer and incubate at room temperature for        15-30 minutes    -   20. Read the plate in pherastar (alpha screen protocol)

Calculations

The percent inhibition is calculated in the excel analysis template andthe IC50 values are subsequently determined using a sigmoidaldose-response curve (variable slope) using GraphPad Prism® 5 software.

Example 2: JAK Activity and IC50 Calculation

A kinase assay with HTRF was used to observe JAK activity and calculatethe IC50s of compounds disclosed herein. HTRF is an enzymatic assay usedto determine the amount of phosphorylated peptide. FRET (FluorescenceResonance Energy Transfer) is based on the transfer of energy betweentwo fluorophores—a donor and an acceptor—when in close proximity.Molecular interactions between biomolecules can be assessed by couplingeach partner with a fluorescent label and by detecting the level ofenergy transfer. The amount of phopshorylated peptide can be detectedusing a combination of a Eu 3+Cryptate labeled anti-phospho residueantibody, SA-XL665 and a biotinylated substrate. The signal isproportional to the concentration of phospho-residues.

Equipment Required

-   -   1. 384-well black plate from Corning (cat #3575)    -   2. Plate centrifuge    -   3. Plate shaker    -   4. 96-well v-bottomed plates from Corning (Cat #3363)    -   5. Single channel and multi-channel pipettes    -   6. Microplate reader (Pherastar)]

Stock and Final Assay Concentrations (FAC)

-   -   1. All reference and test compounds are made at a concentration        of 10 mM in DMSO. Compounds are serially diluted in DMSO and a        FAC starting from 10 μM to 10 point 3 fold serial dilutions is        arrived. For Ruxolitinib the starting FAC is 1 μM. FAC of DMSO        is 1%.    -   2. Enzyme stock and FAC

Enzyme Stock concentration in μM FAC in nM JAK1 3.12 10 JAK2 6 0.5 JAK35.34 1

-   -   -   JAK-1: Invtirogen Cat: PR8767C        -   JAK-2: Invtirogen Cat: PR7820B        -   JAK-3: Invtirogen Cat: PR7507B

    -   3. Substrate (synthetic peptide-Biotinylated-N-terminal        tag-EQEDEPEGDYFEWLE from Biopeptide) stock and FAC

Enzyme Stock concentration in mM FAC in nM JAK1 1 500 JAK2 1 250 JAK3 1500

-   -   4. ATP stock and FAC

Enzyme Stock concentration in mM FAC in nM JAK1 10 25000 JAK2 10 500JAK3 10 500

-   -   -   Adenosine 5′-triphosphate disodium salt hydrate: Sigma Cat:            A26209

    -   5. HTRF reagent stock and FAC        -   Streptavidin-XL665 (Cisbio Cat: 610SAXAC): 1 mg/mL,            streptavidin concentration is 16.6 μM Conc. in assay: 12 nM            (based on streptavidin concentration)        -   Europium-W1024-PT-66 Anti Phospho Tyrosine Ab (Perkin Elmer            Cat: AD0068): Conc. in assay: 0.1 nM [100 ug/ml stock (3.125            uM)].        -   HTRF mix:        -   HTRF buffer: 25 mL        -   SA-XL665: 18 μL        -   Eu-PT66Ab: 1 μl

    -   6. Buffers        -   Base buffer (for 50 ml)

HEPES 60 mM 3 ml NaCl 50 mM 2.5 ml MgCl2 20 mM 1 mL MnCl2 5 mM 250 μLDTT 1M 100 μL BSA (5%) 500 μL Sodium orthovandate 0.1M 50 μL Milli Qwater pH 7.4 42.6 ml

-   -   -   HTRF buffer:        -   50 mM Tris-HCl, pH—7.5        -   100 mM NaCl        -   0.1% BSA        -   0.05% Tween20        -   0.5 mM EDTA

Procedure

To a 384 well black-plate:

-   -   1. Add 17 μL of the buffer to each well of the 384-well black        plate    -   2. Add 8 μl of the diluted compound to each well of the 384-well        plate    -   3. Add 5 μl of the enzyme to each well of the plate    -   4. Add 10 μl of the substrate and ATP mix to all the wells    -   5. Cover with plate sealer    -   6. Spin the plate briefly (640 rpm for 30 s) in a plate        centrifuge.    -   7. Incubate at room temperature for 1 hour on shaker    -   8. After incubation, transfer 5 μl of reaction mix to fresh        wells of a 384-well plate. Add 37.5 μL of the HTRF mix to these        wells.    -   9. Incubate the plate at room temperature on shaker for 45        minutes.    -   10. Take the reading in Pherastar in HTRF mode (ext 337 nm, em        665 & 620 nm)

Calculations

The percent inhibition is calculated in the excel analysis template andthe IC50 values are subsequently determined using a sigmoidaldose-response curve (variable slope) using GraphPad Prism® 5 software.

TABLE 6 BRD4(1) JAK2 BRD4(2) BRD2(1) BRD3(1) BRDT(1) JAK1 JAK3 IC50 IC50IC50 IC50 IC50 IC50 IC50 IC50 Structure (μM) (μM) (μM) (μM) (μM) (μM)(μM) (μM)

NA NA

NA NA

NA NA

NA NA

NA NA

NA NA

NA NA

10.00 NA

7.19 NA

NA NA

NA NA

NA NA

NA NA

NA NA

NA NA

NA NA

1.78 NA

9.74 NA

NA NA

11.18 NA

4.06 NA

NA NA

NA NA

NA NA

NA NA

NA NA

NA NA

NA NA

NA 6.78

NA NA

NA NA

NA NA

NA NA

NA NA

NA 0.0038

0.224 NA

0.211 0.012

NA NA

NA NA

NA NA

NA NA

4.89 NA

NA 0.546

NA NA

NA NA

NA NA

NA NA

NA NA

NA NA

NA NA

5.02 NA

NA NA

NA NA

NA NA

NA NA

NA NA

NA NA

NA NA

NA NA

NA 2.25

3.61 NA

NA NA

NA NA

NA #REF!

0.103 NA

NA NA

NA NA

NA NA

NA NA

NA NA

5.72 5.92

NA NA

7.40 NA

0.094 NA

NA NA

0.609 NA

NA NA

NA 0.0013

0.114 NA

4.40 NA

NA NA

0.344 NA

NA NA

NA NA

NA NA

NA NA

0.376 NA

7.50 NA

NA 0.387

NA NA

NA NA

NA NA

3.23 NA

NA NA

4.56 NA

0.64 NA

NA NA

NA NA

2.39 NA

NA NA

NA NA

NA NA

NA NA

NA NA

NA NA

2.86 4.65

NA NA

0.22 NA

NA 0.0013

0.089 NA

0.526 NA

NA NA

1.098 NA

1.58 NA

NA NA

0.608 NA

2.32 NA

NA NA

0.18 0.01

NA 0.030

NA NA

2.114 NA

NA NA

NA NA

NA NA

0.094 NA 0.309 0.458 0.248 Data aw

0.16 NA 0.293 0.776 0.331 Data aw

0.21 0.01 0.013 0.373 0.213 Data aw

1.005 1.77 2.47 Data aw

0.021 0.063 0.08 Data aw

NA NA

6.31 NA

NA NA

NA NA

NA NA

1.34 NA

NA NA

NA NA

NA NA

2.75 NA

2.17 NA

NA NA

2.67 NA

NA NA

2.38 NA

NA NA

NA 0.0031

0.019 NA

0.221 0.007

NA NA

NA NA

1.83 NA

2.20 NA

0.133 0.008

0.096 NA

NA NA

0.47 NA 1.13 0.636 3.2 1.8 NA

0.155 0.012

0.087 0.024 0.030 0.157 0.092 0.131 1.01

0.194 NA

3.20 NA

0.581 0.0018

0.318 NA

0.206 NA

7.50 NA

0.066 NA

0.42 0.0023 0.451 0.682 0.853 0.638 0.185

0.118 0.004 0.073 0.448 0.366 0.23

0.0934 0.0118 0.112 0.254 0.183 0.228 0.313

6.30 NA 5.3 0.79 8.4 NA NA

0.79 0.0014 0.736 0.678 1.4 1.4 0.220

0.42 0.0023

1.98 10

2.83 10

5.80 10

3.27 10

2.68 10

10 10

0.90 10

0.17 10

0.255 0.01

10 10

0.22 0.0074 0.175 0.70 0.27 0.696 0.243 0.127

10 10

3.03 10

0.87 10

0.18 8.93

10 10

0.94 10

0.59 10

1.542 10

5.156 10

0.257 10

0.22 0.007 0.073 0.448 0.366 0.23 NA

1.21 10

1.68 0.032

0.122 3.01

0.242 0.0058

0.164 0.008

0.26 4.17

0.355 0.0025 0.729 1.9 0.825 2.5 0.244 0.069

1.41 0.032

0.434 0.018 0.487 2.86 0.652 1.11 0.424 0.125

0.228 0.010

1.02 0.0082

0.152 0.012 0.254 1.58 0.5 0.632 0.418 0.067

10 10

2.33 0.003

1.30 0.038

10 0.003

5.01 1.66

1.94 0.04

10 10

1.13 0.008

0.28 0.009

10 10

0.284 1000

0.128 0.035 0.0675 0.49 0.109 0.182 0.972 0.105

0.677 0.002 0.574 2.961 0.914 1.21 0.188 0.015

1.46 0.0043 1.349 6.207 1.735 2.633 0.031

1.49 0.0153

3.055 0.0197

1.043 0.0143

5.529 0.0244

0.68 0.23

0.641 0.176

0.24 0.0115 0.156 0.314 0.089 0.23 0.057 0.103

0.676 0.0204 0.325 1.4 0.57 0.322 0.473 0.1

0.394 0.01

1.353 0.005

0.208 0.101

2.2 0.031

1.70 0.043

0.481 0.165

0.776 0.035

0.856 0.013

1.8 0.078

0.431 0.0052 0.13 0.743 0.161 0.363 0.293 0.082

0.722 0.011

0.173 0.0073 0.062 0.632 0.164 0.406 0.4 0.081

0.378 0.0189 0.491 1.15 0.248 1 1.1 0.338

1.6 2.8

0.451 0.006

0.166 0.013

0.407 0.026

0.581 0.074

1.9 0.044

2.72 0.051

3.21 0.071

2..5 0.045

5.73 24.94

1.13 0.152

0.916 0.176

0.475 1.601

1.59 0.069

2.1 0.04

4.01 0.182

0.094 359.7

1.81 0.015

10 0.008

0.866 0.014

0.235 0.043

0.228 0.188

7.075 10

10 0.011

0.398 0.018 0.099 0.467 0.078 0.312 0.206 0.242

0.372 0.177

0.989 0.029

0.649 0.024

1.01 0.01

0.246 0.02 0.029 0.318 0.117 0.189 1.1 0.292

0.771 0.028

0.402 0.0028 0.128 0.548 0.142 0.32 0.275 0.112

3.2 0.019

10 0.456

0.278 0.0066

0.272 0.09

10 0.14

1.8 0.008

0.774 10

1.7 0.074

1.1 0.009

0.561 0.022

0.258 0.082

10 0.0007

0.134 0.13

0.406 0.064

0.123 0.17

0.063 0.027 0.088 0.231 0.049 0.14 2.1 0.193

0.205 0.05 0.067 0.576 0.117 0.268 0.178 0.253

0.19 0.005

10 0.054

0.149 0.062

0.131 0.003

0.682 0.02

0.153 0.027

0.407 0.024

0.316 0.0093

0.643 0.239

10 2.4

10 0.00018

0.193 0.359

0.145 0.051

4.6 0.04

8.3 0.12

0.105 0.265

0.138 0.01

0.131 0.003

1.4 0.4

0.735 0.123

1.1 0.12

0.577 0.072

8.3 0.003

0.141 0.006

0.93 0.012

10 10

0.142 0.251

0.295 0.142

0.155 0.007

0.063 0.027

10 0.0006

3.8 0.01

0.636 0.006

0.377 0.0044

0.491 0.129

0.375 0.0048

0.393 0.018

0.208 0.014

1.2 10

0.315 10

0.063 0.043

0.229 0.0065

NA NA

0.306 0.013

1.4 0.0047

1.5 0.005

0.368 0.003

0.143 0.083

0.366 0.014

0.963 0.024

0.321 0.137

0.297 0.004

0.393 0.018

1.5 0.103

0.607 0.002

0.295 0.002 0.193 0.506 0.181 0.308 0.169 0.061

0.108 0.008 0.091 0.292 0.11 0.177 0.927 0.097

0.233 0.011 0.203 0.605 0.196 0.329 0.734 0.06

0.8 0.07

0.248 0.02

0.06 0.033 0.064 0.216 0.059 0.118 2.1 0.272

0.228 0.036

0.125 0.076

0.248 0.0096

0.174 0.008

3.2 0.035

0.318 0.005

0.162 0.051

0.3 0.006

0.571 0.014

0.854 0.037

0.421 0.002

0.75 0.037

0.56 0.001

0.58 0.009

0.079 0.04 0.085 0.235 0.081 0.185 3.7 0.206

0.268 0.008

0.105 0.012

0.356 0.004

0.357 0.006

0.337 0.022

0.431 0.002

0.234 0.029

0.298 0.012

1.8 0.007

0.383 0.056

0.766 0.005

0.538 0.017

0.123 0.039 0.086 0.36 0.097 0.185 1.5 0.173

0.15 0.052 0.088 0.42 0.302 9.9 0.608

0.192 0.01 0.092 0.67 0.154 0.223 1.2 0.082

0.308 0.021

2.3 0.05

0.22 0.007

0.125 0.052 0.054 0.473 0.158 0.268 0.992 0.403

0.082 0.028 0.054 0.369 0.123 0.194 0.587 0.334

0.109 0.002 0.131 0.489 0.1 0.281 0.044 0.018

0.115 0.061 0.12 0.353 0.083 0.292 10 0.285

0.2 0.027

1.3 0.079

What is claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof; wherein: R¹ isH, halogen, alkyl, haloalkyl, hydroxyl, alkylhydroxyl, alkoxy,haloalkoxy, or —NR^(a)R^(b); R² and R³ are each independently H oralkyl; R⁴ and R⁵ are each independently H, halogen, hydroxyl or alkyl;R⁶ and R⁷ are each independently H, halogen, hydroxyl or alkyl; oralternatively, R⁶ and R³ together or R⁷ and R³ together forms asaturated, unsaturated, or partially saturated, 5- or 6-membered ring;ring A and ring B are each aromatic; Z¹ is C or N; Z² is C, CR⁸, or N;Z³ and Z⁴ are each independently C, CR⁸, N, or S; provided that at leastone of Z¹, Z², Z³, and Z⁴ is N or S and at most two of Z¹, Z², Z³, andZ⁴ is N; R⁸ is H, halogen, or alkyl; L is a bond or —CH₂—; W is—S(O)_(m)R⁹, —P(O)₂R⁹, or —P(═S)₂R⁹; R⁹ is alkyl, cycloalkyl, or aryl,wherein cycloalkyl and aryl is optionally substituted with one or moreof halogen or alkyl; Y is selected from

in Y¹ and Y², R¹⁰ and R¹⁴ are each independently H, halogen, hydroxyl,alkyl, or alkoxy; in Y¹, R¹¹, R¹² and R¹³ are each independently H,halogen, alkyl, alkoxy, heterocyclyl, —(CH₂)_(n)—C(O)NR^(a)R^(c),—(CH₂)_(n)—NR^(a)C(O)R^(d), —(CH₂)_(n)—C(O)(CH₂)_(n)—, —NR^(a)R^(b),—NR^(a)-alkylene-NR^(a)R^(b), or—(CH₂)_(n)—C(O)NR^(a)-alkylene-NR^(a)R^(b); or in Y², R¹¹ is H, halogen,hydroxyl or alkyl; in Y², ring C is a monocyclic, bicyclic, or tricyclic5- to 12-membered heterocycle containing at least one atom selected fromN, O, or S, wherein ring C is optionally substituted with R¹⁵; R^(a) andR^(b) are each independently, H or alkyl; R^(c) is H, alkyl,-alkyl-NR^(a)R^(b), or heterocyclyl; R^(d) is alkyl, -alkyl-NR^(a)R^(b),or heterocyclyl; wherein hetercocycyl in R¹¹, R¹², R¹³, R^(c), and R^(d)is each independently optionally substituted with R¹⁵; R¹⁵ is halogen,hydroxyl, alkyl, alkylhydroxyl, oxo, —C(O)-alkyl, —C(O)OR^(a);—NR^(a)C(O)-alkyl, —(CH₂)_(n)—C(O)NR^(a)R^(b), —NR^(a)R^(b); or—S(O)_(n)-alkyl, n is 0, 1, or 2; and m is 0, 1, or 2; wherein thecompound is not


2. The compound of claim 1, wherein Z² is N and Z¹, Z³, and Z⁴ are eachindependently C or CR⁸.
 3. The compound of claim 1, wherein Z¹ is N andZ², Z³, and Z⁴ are each independently C or CR⁸.
 4. The compound of claim1, wherein Z¹ and Z³ are each N, and Z² and Z⁴ are each independently Cor CR⁸.
 5. The compound of claim 1, wherein Z¹ and Z⁴ are each N, and Z³and Z⁴ are each independently C or CR⁸.
 6. The compound of claim 1having the formula (II)

or a pharmaceutically acceptable salt or solvate thereof.
 7. Thecompound of any one of claims 1-6, wherein W is —S(O)₂R⁹.
 8. Thecompound of claim 7, wherein R⁹ is C₁-C₆ alkyl or C₃-C₆ alkyl, eachoptionally substituted.
 9. The compound of any one of claims 1-7,wherein L is a bond.
 10. The compound of claim 1 having the formula(III)


11. The compound of any one of claims 1-10, wherein R² and R³ are each Hor C₁-C₃ alkyl.
 12. The compound of any one of claims 1-11 wherein R⁴and R⁵ are each H.
 13. The compound of any one of claims 1-12, whereinR⁶ and R⁷ are each independently H or halogen.
 14. The compound of anyone of claims 1-12, wherein R⁶ and R³ together forms a saturated,unsaturated, or partially saturated, 5- or 6-membered ring.
 15. Thecompound of claim 14, wherein, R⁶ and R³ together forms a saturated5-membered ring.
 16. The compound of any one of claims 1-15, wherein,R¹⁰ and R¹⁴ are each H.
 17. The compound of any one of claims 1-16,wherein, at least one of R¹¹ and R¹³ is a halogen.
 18. The compound ofany one of claims 1-17, wherein Y is Y¹.
 19. The compound of claim 18,wherein one of R¹¹, R¹² and R¹³ is an optionally substitutedheterocyclyl.
 20. The compound of claim 19, wherein the heterocyclyl isselected from piperidine, piperazine, hexahydropyrimidine, morpholine,tetrahydropyran, thiane, or thiomorpholine, each optionally substituted.21. The compound of claim 19, wherein the heterocyclyl is a bicycle. 22.The compound of claim 19, wherein the heterocyclyl is selected from

each of which is optionally substituted with R¹⁵.
 23. The compound ofclaim 18, wherein one of R¹¹, R¹² and R¹³ is —(CH₂)_(n)—C(O)NR^(a)R^(c),—(CH₂)_(n)—NR^(a)C(O)R^(d), —(CH₂)_(n)—C(O)(CH₂)_(n)—, —NR^(a)R^(b),—NR^(a)-alkylene-NR^(a)R^(b), or—(CH₂)_(n)—C(O)NR^(a)-alkylene-NR^(a)R^(b);
 24. The compound of claim23, wherein one of R¹¹, R¹² and R¹³ is —NR^(a)-alkylene-NR^(a)R^(b) or—(CH₂)_(n)—C(O)NR^(a)-alkylene-NR^(a)R^(b).
 25. The compound of any oneof claims 1-17, wherein Y is Y².
 26. The compound of claim 25, whereinY² is selected from:

each of which is optionally substituted with R¹⁵; and R¹⁶ is H or C₁-C₃alkyl.
 27. The compound of claim 10, wherein R⁹ is C₁-C₆ alkyl or C₃-C₆alkyl, each optionally substituted.
 28. The compound of claim 1 havingthe formula (IV)

or a pharmaceutically acceptable salt or solvate thereof.
 29. Thecompound of claim 28, wherein W is —S(O)₂R⁹.
 30. The compound of claim29, wherein R⁹ is C₁-C₆ alkyl or C₃-C₆ alkyl, each optionallysubstituted.
 31. The compound of any one of claim 29 or 30, wherein L isa bond.
 32. The compound of claim 1 having the formula (V)

or a pharmaceutically acceptable salt or solvate thereof.
 33. Thecompound of any one of claims 28-32, wherein R² and R³ are each H orC₁-C₃ alkyl.
 34. The compound of any one of claims 28-33 wherein R⁴ andR⁵ are each H.
 35. The compound of any one of claims 31-37, wherein R⁶and R⁷ are each independently H or halogen.
 36. The compound of any oneof claims 28-35, wherein, R¹⁰ and R¹⁴ are each H.
 37. The compound ofany one of claims 28-36, wherein, at least one of R¹¹ and R¹³ is ahalogen.
 38. The compound of any one of claims 28-37, wherein Y is Y.39. The compound of claim 38, wherein one of R¹¹, R¹² and R¹³ is anoptionally substituted heterocyclyl.
 40. The compound of claim 39,wherein the heterocyclyl is selected from piperidine, piperazine,hexahydropyrimidine, morpholine, tetrahydropyran, thiane, orthiomorpholine, each optionally substituted.
 41. The compound of claim40, wherein the heterocyclyl is a bicycle.
 42. The compound of claim 41,wherein the heterocyclyl is selected from

each of which is optionally substituted with R⁵.
 43. The compound ofclaim 38, wherein one of R¹¹, R¹² and R¹³ is —(CH₂)_(n)—C(O)NR^(a)R^(c),—(CH₂)_(n)—NR^(a)C(O)R^(d), —(CH₂)_(n)—C(O)(CH₂)_(n)—, —NR^(a)R^(b),—NR^(a)-alkylene-NR^(a)R^(b), or—(CH₂)_(n)—C(O)NR^(a)-alkylene-NR^(a)R^(b);
 44. The compound of claim43, wherein one of R¹¹, R¹² and R¹³ is —NR^(a)-alkylene-NR^(a)R^(b) or—(CH₂)_(n)—C(O)NR^(a)-alkylene-NR^(a)R^(b).
 45. The compound of any oneof claims 28-37, wherein Y is Y².
 46. The compound of claim 45, whereinY² is selected from:

each of which is optionally substituted with R¹⁵; and R¹⁶ is H or C₁-C₃alkyl.
 47. The compound of any one of claims 1-47 having aBRD4-inhibiting activity corresponding to an IC₅₀ of 10 μM or less. 48.The compound of any one of claims 1-46 having JAK2 tyrosine kinaseinhibiting activity corresponding to an IC₅₀ of 0.1 μM or less.
 49. Thecompound of claim 47 having JAK2 tyrosine kinase inhibiting activitycorresponding to an IC₅₀ of 0.01 μM or less.
 50. The pharmaceuticalcomposition comprising a compound of any one of claims 1-49, furthercomprising one additional therapeutically active agent.
 51. A method oftreating a disease or condition responsive to the inhibition of abromodomain-containing protein comprising administering to the subjectin need thereof, a therapeutically effective amount of a compound of anyone of claims 1-50, or a pharmaceutically acceptable salt thereof. 52.The method of claim 51, wherein the bromodomain-containing protein isBRD4.
 53. The method of claim 51 or claim 52, wherein the subject ishuman.
 54. The method of any one of claims 51-53, wherein the disease orcondition is cancer.
 55. The method of claim 54, wherein the cancer isselected from one or more of the group consisting of bladder cancer,brain cancer, breast cancer, colorectal cancer, leukemia, cervicalcancer, gastrointestinal cancer, genitourinary cancer, head and neckcancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer,renal cancer, skin cancer, and testicular cancer.
 56. The method of anyone of claims 51-53, wherein the disease or condition is is leukemia.57. A method of treating a disease or condition responsive to theinhibition of a JAK2 tyrosine kinase comprising administering to thesubject in need thereof, a therapeutically effective amount of acompound of any one of claims 1-49, or a pharmaceutically acceptablesalt thereof.
 58. The method of claim 57, wherein the subject is human.59. The method of claim 57 or claim 58, wherein the disease or conditionis cancer.
 60. The method of claim 59, wherein the cancer is selectedfrom one or more of the group consisting of bladder cancer, braincancer, breast cancer, colorectal cancer, leukemia, cervical cancer,gastrointestinal cancer, genitourinary cancer, head and neck cancer,lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renalcancer, skin cancer, and testicular cancer.
 61. The method of claim 57or claim 58, wherein the disease or condition is leukemia.
 62. Acompound of formula (X):

or a pharmaceutically acceptable salt or solvate thereof; wherein: Z¹,Z² and Z³ are each S, N or CR⁸, provided that at least one of Z¹, Z² orZ³ is N or S and at most two of Z¹, Z² or Z³ is N or S; ring A and ringB are each aromatic; V is

L is a bond or —CH₂—; W is —S(O)_(m)R⁹, —P(O)₂R⁹, or —P(═S)₂R⁹; R²,R^(2a) and R³ are each independently H or alkyl; R⁴ and R⁵ are eachindependently H, halogen, hydroxyl or alkyl; R⁶ and R⁷ are eachindependently H, halogen, hydroxyl or alkyl; or alternatively, R⁶ and R³together or R⁷ and R³ together forms a saturated, unsaturated, orpartially saturated, 5- or 6-membered ring; R⁸ is H, halogen, or alkyl;R⁹ is alkyl, cycloalkyl, or aryl, wherein cycloalkyl and aryl isoptionally substituted with one or more of halogen or alkyl; Y isselected from

in Y¹ and Y², R¹⁰ and R¹⁴ are each independently H, halogen, hydroxyl oralkyl; in Y¹, R¹¹, R¹² and R¹³ are each independently H, halogen, alkyl,alkoxy, heterocyclyl, —(CH₂)_(n)—C(O)NR^(a)R^(c),—(CH₂)_(n)—NR^(a)C(O)R^(d), —(CH₂)_(n)—C(O)(CH₂)_(n)—, —NR^(a)R^(b),—NR^(a)-alkylene-NR^(a)R^(b), or—(CH₂)_(n)—C(O)NR^(a)-alkylene-NR^(a)R^(b); or in Y², R¹¹ is H, halogen,hydroxyl or alkyl; in Y², ring C is a monocyclic, bicyclic, or tricyclic5- to 12-membered heterocycle containing at least one atom selected fromN, O, or S, wherein ring C is optionally substituted with R¹⁵; in Y³,R¹⁰, R¹¹, R¹³ and R¹⁴ are each H, halogen, hydroxyl or alkyl; in Y³, R¹⁶is H or alkyl; in Y⁴, R¹⁰, R¹³ and R¹⁴ are each H, halogen, hydroxyl oralkyl; in Y⁴, Z⁴ is NR^(a) or O; in Y³ and Y⁴, M is a bond or —CH₂—;R^(a) and R^(b) are each independently, H or alkyl; R^(c) is H, alkyl,-alkyl-NR^(a)R^(b), or heterocyclyl; R^(d) is alkyl, -alkyl-NR^(a)R^(b),or heterocyclyl; wherein hetercocycyl in R¹¹, R¹², R¹³, R^(c), and R^(d)is each independently optionally substituted with R¹⁵; R¹⁵ is halogen,hydroxyl, alkyl, alkylhydroxyl, oxo, —C(O)-alkyl, —C(O)OR^(a);—NR^(a)C(O)-alkyl, —(CH₂)_(n)—C(O)NR^(a)R^(b), —NR^(a)R^(b); or—S(O)_(n)-alkyl, n is 0, 1, or 2; and m is 0, 1, or
 2. 63. The compoundof claim 62, wherein Z¹, Z² and Z³ are each S or CR⁸, wherein exactlyone of Z¹, Z² or Z³ is S.
 64. The compound of claim 63, wherein Z¹ is S.65. The compound of claim 63, wherein Z³ is S.
 66. The compound of claim63, wherein V is V².
 67. The compound of claim 66, wherein R^(2a) is Hand R³ is alkyl.
 68. The compound of claim 67, wherein R²a is H and R³is C3-C6 cycloalkyl.
 69. The compound of claim 63, wherein V is


70. The compound of claim 63, wherein V is V¹.
 71. The compound of claim70, wherein W is —S(O)₂R⁹.
 72. The compound of claim 71, wherein R⁹ isC₁-C₆ alkyl or C₃-C₆ alkyl, each optionally substituted.
 73. Thecompound of any one of claims 70-72, wherein L is a bond.
 74. Thecompound of any one of claims 70-73, wherein R⁴ and R⁵ are each H. 75.The compound of any one of claims 70-74, wherein R⁶ and R⁷ are eachindependently H or halogen.
 76. The compound of any one of claims 70-73,wherein R⁶ and R³ together forms a saturated, unsaturated, or partiallysaturated, 5- or 6-membered ring.
 77. The compound of claim 76, wherein,R⁶ and R³ together forms a saturated 5-membered ring.
 78. The compoundof any one of claims 63-77, wherein Y is Y¹.
 79. The compound of claim78, wherein one of R¹¹, R¹² and R¹³ is an optionally substitutedheterocyclyl.
 80. The compound of claim 79, wherein the heterocyclyl isselected from piperidine, piperazine, hexahydropyrimidine, morpholine,tetrahydropyran, thiane, or thiomorpholine, each optionally substituted.81. The compound of claim 79, wherein the heterocyclyl is a bicycle. 82.The compound of claim 79, wherein the heterocyclyl is selected from

each of which is optionally substituted with R¹⁵.
 83. The compound ofclaim 78, wherein one of R¹¹, R¹² and R¹³ is —(CH₂)_(n)—C(O)NR^(a)R^(c),—(CH₂)_(n)—NR^(a)C(O)R_(d), —(CH₂)_(n)—C(O)(CH₂)_(n)—, —NR^(a)R^(b),—NR^(a)-alkylene-NR^(a)R^(b), or—(CH₂)_(n)—C(O)NR^(a)-alkylene-NR^(a)R^(b);
 84. The compound of claim83, wherein one of R¹¹, R¹² and R¹³ is —NR^(a)-alkylene-NR^(a)R^(b) or—(CH₂)_(n)—C(O)NR^(a)-alkylene-NR^(a)R^(b).
 85. The compound of any oneof claims 63-77, wherein Y is Y².
 86. The compound of claim 85, whereinY² is selected from:

each of which is optionally substituted with R¹⁵; and R¹⁶ is H or C₁-C₃alkyl.
 87. The compound of any one of claims 63-77, wherein Y is Y³. 88.The compound of claim 87, wherein R¹⁰, R¹¹, R¹³ and R¹⁴ are each H. 89.The compound of claim 87 or 88, wherein R¹⁶ is H or methyl.
 90. Thecompound of any one of claims 87-89, wherein M is —CH₂—.
 91. Thecompound of any one of claims 63-77, wherein Y is Y⁴.
 92. The compoundof claim 91, wherein R¹⁰, R¹³ and R¹⁴ are each H.
 93. The compound ofclaim 91 or 92, wherein Z⁴ is NH or NCH₃.
 94. The compound of claim 62selected from:

or a pharmaceutically acceptable salt or solvate thereof.
 95. Thecompound of claim 62, wherein the compound is

or a pharmaceutically acceptable salt or solvate thereof.
 96. Thecompound of any one of claims 62-95 having a BRD4-inhibiting activitycorresponding to an IC₅₀ of 10 μM or less.
 97. The compound of any oneof claims 62-95 having JAK2 tyrosine kinase inhibiting activitycorresponding to an IC₅₀ of 0.1 μM or less.
 98. The compound of claim 96having JAK2 tyrosine kinase inhibiting activity corresponding to an IC₅₀of 1.0 μM or less.
 99. The pharmaceutical composition comprising acompound of any one of claims 62-98, further comprising one additionaltherapeutically active agent.
 100. A method of treating a disease orcondition responsive to the inhibition of a bromodomain-containingprotein comprising administering to the subject in need thereof, atherapeutically effective amount of a compound of any one of claims62-98, or a pharmaceutically acceptable salt thereof.
 101. The method ofclaim 100, wherein the bromodomain-containing protein is BRD4.
 102. Themethod of claim 100 or claim 101, wherein the subject is human.
 103. Themethod of any one of claims 100-102, wherein the disease or condition iscancer.
 104. The method of claim 103, wherein the cancer is selectedfrom one or more of the group consisting of bladder cancer, braincancer, breast cancer, leukemia, colorectal cancer, cervical cancer,gastrointestinal cancer, genitourinary cancer, head and neck cancer,lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renalcancer, skin cancer, and testicular cancer.
 105. The method of any oneof claims 100-102, wherein the disease or condition is leukemia.
 106. Amethod of treating a disease or condition responsive to the inhibitionof a JAK2 tyrosine kinase comprising administering to the subject inneed thereof, a therapeutically effective amount of a compound of anyone of claims 62-95, or a pharmaceutically acceptable salt thereof. 107.The method of claim 106, wherein the subject is human.
 108. The methodof claim 106 or claim 107, wherein the disease or condition is cancer.109. The method of claim 108, wherein the cancer is selected from one ormore of the group consisting of bladder cancer, brain cancer, breastcancer, leukemia, colorectal cancer, cervical cancer, gastrointestinalcancer, genitourinary cancer, head and neck cancer, lung cancer, ovariancancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer,and testicular cancer.